|
Ability to displace [3H]-DPAT from 5-hydroxytryptamine 1A receptor in homogenates of bovine hippocampus.
|
None
|
534.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.
Year : 1992
Volume : 35
Issue : 6
First Page : 1076
Last Page : 1092
Authors : Moon MW, Morris JK, Heier RF, Chidester CG, Hoffmann WE, Piercey MF, Althaus JS, Von Voigtlander PF, Evans DL, Figur LM.
Abstract : The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
|
Binding affinity was measured on cloned Human 5-hydroxytryptamine 1A receptor which is labeled by [3H]8-OH-DPAT
|
Homo sapiens
|
296.0
nM
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.
Year : 2000
Volume : 43
Issue : 7
First Page : 1339
Last Page : 1349
Authors : Linnanen T, Brisander M, Unelius L, Sundholm G, Hacksell U, Johansson AM.
Abstract : The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.
|
In vitro binding affinity towards cloned human 5-hydroxytryptamine 1A receptor expressed in Chinese hamster ovary (CHO) cells using [3H]8-OH-DPAT as radioligand
|
None
|
296.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Serotonergic and dopaminergic activities of rigidified (R)-aporphine derivatives.
Year : 2001
Volume : 11
Issue : 3
First Page : 367
Last Page : 370
Authors : Linnanen T, Brisander M, Mohell N, Johansson AM.
Abstract : Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.
|
In vitro displacement of [3H]8-OH-DPAT binding to rat hippocampal 5-hydroxytryptamine 1A receptor
|
None
|
296.0
nM
|
|
Journal : J. Med. Chem.
Title : 11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3503
Last Page : 3513
Authors : Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
|
In vitro affinity at 5-hydroxytryptamine 1A receptor of rat hippocampus by [3H]8-OH-DPAT displacement.
|
None
|
296.0
nM
|
|
Journal : J. Med. Chem.
Title : 10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3491
Last Page : 3502
Authors : Hedberg MH, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
|
Displacement of [3H]8-OH-DPAT from human 5-hydroxytryptamine 1A receptor expressed in CHO cells
|
Homo sapiens
|
296.0
nM
|
|
Journal : J. Med. Chem.
Title : Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: selective serotonin 5-HT(7) receptor antagonists.
Year : 2001
Volume : 44
Issue : 9
First Page : 1337
Last Page : 1340
Authors : Linnanen T, Brisander M, Unelius L, Rosqvist S, Nordvall G, Hacksell U, Johansson AM.
|
Ability to displace [3H]8-OH-DPAT binding to rat hippocampal 5-hydroxytryptamine 1A receptor
|
None
|
296.0
nM
|
|
Journal : J. Med. Chem.
Title : (R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1995
Volume : 38
Issue : 4
First Page : 647
Last Page : 658
Authors : Hedberg MH, Johansson AM, Nordvall G, Yliniemelä A, Li HB, Martin AR, Hjorth S, Unelius L, Sundell S, Hacksell U.
Abstract : (R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
|
Binding affinity against Rat 5-hydroxytryptamine 7 receptor using [3H]5-HT
|
Rattus norvegicus
|
188.0
nM
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.
Year : 2000
Volume : 43
Issue : 7
First Page : 1339
Last Page : 1349
Authors : Linnanen T, Brisander M, Unelius L, Sundholm G, Hacksell U, Johansson AM.
Abstract : The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.
|
Displacement of [3H]5-HT from rat 5-hydroxytryptamine 7 receptor expressed in CHO cells
|
Rattus norvegicus
|
188.0
nM
|
|
Journal : J. Med. Chem.
Title : Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: selective serotonin 5-HT(7) receptor antagonists.
Year : 2001
Volume : 44
Issue : 9
First Page : 1337
Last Page : 1340
Authors : Linnanen T, Brisander M, Unelius L, Rosqvist S, Nordvall G, Hacksell U, Johansson AM.
|
In vitro binding affinity towards cloned rat 5-hydroxytryptamine 7 receptor using [3H]5-HT as radioligand
|
None
|
188.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Serotonergic and dopaminergic activities of rigidified (R)-aporphine derivatives.
Year : 2001
Volume : 11
Issue : 3
First Page : 367
Last Page : 370
Authors : Linnanen T, Brisander M, Mohell N, Johansson AM.
Abstract : Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.
|
Alpha-2 adrenergic receptor activity assessed in vitro for displacement of [3H]clonidine from specific binding sites on rat striatal membranes
|
None
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.
Year : 1984
Volume : 27
Issue : 12
First Page : 1607
Last Page : 1613
Authors : Jones JH, Anderson PS, Baldwin JJ, Clineschmidt BV, McClure DE, Lundell GF, Randall WC, Martin GE, Williams M, Hirshfield JM.
Abstract : A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.
|
In vitro inhibitory activity against alpha-2 adrenergic receptor from rat brain minus cerebellum using [3H]clonidine as radioligand
|
None
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine.
Year : 1985
Volume : 28
Issue : 3
First Page : 367
Last Page : 375
Authors : Nordmann R, Petcher TJ.
Abstract : A synthesis of all four diastereoisomeric 3-(tert-butoxycarbonyl)-1,6-dimethoxyoctahydrobenzo[g]quinolines 13a-d is presented. The two trans isomers 13b and 13c have been converted to tricyclic analogues 20 (CV 205-502) and 26 (205-503) of the potent dopaminomimetic ergolines CQ 32-084 and pergolide, respectively. These two compounds combine the essential moiety of apomorphine with the important 8-substituents of ergolines. Preliminary pharmacological evaluation of 20 and 26 suggests that these novel dopamine agonists combine the specificity of apomorphine with the potency, long duration of action, and good oral activity of the ergolines.
|
In vitro inhibitory activity was evaluated against,[3H]clonidine (Clon) rat brain minus cerebellum Alpha-2 adrenergic receptor
|
None
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3 alpha, 4a alpha, 10a beta)-1,2,3,4,4a,5,10,10a- -octahydro-6-hydroxy-1-propyl-3-benzo[g]quinolinyl]sulfamide.
Year : 1985
Volume : 28
Issue : 10
First Page : 1540
Last Page : 1542
Authors : Nordmann R, Widmer A.
Abstract : The synthesis and preliminary pharmacological evaluation of the optical antipodes of the title compound (+/-)-1 (CV 205-502) is presented. The dopaminomimetic activity is shown to reside entirely in the (-) enantiomer. Crystallographic analysis has proven that the absolute configuration of the active (-) enantiomer corresponds to that of its ergoline analogue 3 (CQ 32-084) and of apomorphine (5).
|
Inhibition of [3H]apomorphine binding to calf caudate membrane preparation (p4)
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines, 36. Dopamine receptor interactions of trihydroxyaporphines. Synthesis, radioreceptor binding, and striatal adenylate cyclase stimulation of 2,10,11-trihydroxyaporphines in comparison with other hydroxylated aporphines.
Year : 1981
Volume : 24
Issue : 12
First Page : 1440
Last Page : 1445
Authors : Neumeyer JL, Arana GW, Law SJ, Lamont JS, Kula NS, Baldessarini RJ.
Abstract : The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptors. Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described. Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of [3H]apomorphine (APO) and [3H]spiroperidol (SPR) with a subcellular fraction (P4) of caudate nucleus from bovine brain. In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue. The rank order of displacement of [3H]APO by potent aporphines (IC50 less than or equal to 30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis. Potency orders against two ligands were dissimilar; for example, increasing the size of N6-alkyl substituents increased potency vs. [3H]SPR but not vs. [3H]APO binding. Moreover, [3H]SPR binding correlated poorly with cyclase activity or [3H]APO binding, suggesting a closer relationship of [3H]APO binding to dopamine-sensitive adenylate cyclase activity.
|
Inhibition of [3H]spiroperidol binding to calf caudate membrane preparation (p4)
|
None
|
860.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines, 36. Dopamine receptor interactions of trihydroxyaporphines. Synthesis, radioreceptor binding, and striatal adenylate cyclase stimulation of 2,10,11-trihydroxyaporphines in comparison with other hydroxylated aporphines.
Year : 1981
Volume : 24
Issue : 12
First Page : 1440
Last Page : 1445
Authors : Neumeyer JL, Arana GW, Law SJ, Lamont JS, Kula NS, Baldessarini RJ.
Abstract : The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptors. Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described. Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of [3H]apomorphine (APO) and [3H]spiroperidol (SPR) with a subcellular fraction (P4) of caudate nucleus from bovine brain. In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue. The rank order of displacement of [3H]APO by potent aporphines (IC50 less than or equal to 30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis. Potency orders against two ligands were dissimilar; for example, increasing the size of N6-alkyl substituents increased potency vs. [3H]SPR but not vs. [3H]APO binding. Moreover, [3H]SPR binding correlated poorly with cyclase activity or [3H]APO binding, suggesting a closer relationship of [3H]APO binding to dopamine-sensitive adenylate cyclase activity.
|
Binding affinity was measured on cloned Human D2A Receptor which is labeled by [3H]raclopride
|
None
|
41.6
nM
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.
Year : 2000
Volume : 43
Issue : 7
First Page : 1339
Last Page : 1349
Authors : Linnanen T, Brisander M, Unelius L, Sundholm G, Hacksell U, Johansson AM.
Abstract : The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.
|
Affinity of the Compound for Dopamine D1 receptor in rat striatal membrane was determined in vitro using Dopamine Antagonist [3H]SCH-23390 as ligand.
|
None
|
384.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 4,5,6,7-tetrahydrobenzothiazole dopamine agonists display very low stereoselectivity in their interaction with dopamine receptors.
Year : 1991
Volume : 1
Issue : 4
First Page : 189
Last Page : 192
Authors : Jaen JC, Caprathe BW, Wise LD, Smith SJ, Pugsley TA, Heffner TG, Meltzer LT
|
Binding affinity against Dopamine receptor D1 from rat brain corpus striatum membrane
|
Rattus norvegicus
|
444.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinity of (R)-(-)-2-fluoro-N-n-propylnorapomorphine: a highly potent and selective dopamine D2 agonist.
Year : 1990
Volume : 33
Issue : 12
First Page : 3122
Last Page : 3124
Authors : Neumeyer JL, Gao YG, Kula NS, Baldessarini RJ.
|
In vitro binding affinity to Dopamine receptor D1 in rat striatal membranes using D1 antagonist [3H]SCH-23390
|
None
|
384.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and dopaminergic activity of the enantiomers of 6-methyl-4,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine (PD 128483).
Year : 1991
Volume : 1
Issue : 10
First Page : 539
Last Page : 544
Authors : Jaen JC, Caprathe BW, Wise LD, Pugsley TA, Meltzer LT, Heffner TG
|
Compound was tested in vitro for binding affinity towards Dopamine receptor D1 in rat striatal membrane by using [3H]-SCH- 23390 as radioligand
|
None
|
384.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 3.6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine.
Year : 1991
Volume : 34
Issue : 9
First Page : 2736
Last Page : 2746
Authors : Caprathe BW, Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT, Parvez M.
Abstract : A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
|
Compound was evaluated for the ability to displace [3H]spiperone at Dopamine receptor D2 in porcine anterior pituitary gland as high affinity state
|
Sus scrofa
|
0.66
nM
|
|
Journal : J. Med. Chem.
Title : 2-Haloaporphines as potent dopamine agonists.
Year : 1989
Volume : 32
Issue : 6
First Page : 1198
Last Page : 1201
Authors : Ramsby S, Neumeyer JL, Grigoriadis D, Seeman P.
Abstract : The synthesis of 2-amino- and 2-halo-substituted aporphines is described. The key step is the substitution of a hydroxy group in the 2-position with an amino group effected by a Smiles rearrangement reaction of the 2-methylpropanamide derivative 6. The affinity of the new compounds for the dopamine D-2 receptor in the anterior pituitary gland was evaluated. 2-Fluoroapomorphine was the most potent compound, being 1.5 times more potent than (-)-apomorphine. The structure-activity relationships are discussed in relation to a previously proposed receptor model.
|
Compound was evaluated for the ability to displace [3H]spiperone at Dopamine receptor D2 in porcine anterior pituitary gland as low affinity state
|
Sus scrofa
|
127.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-Haloaporphines as potent dopamine agonists.
Year : 1989
Volume : 32
Issue : 6
First Page : 1198
Last Page : 1201
Authors : Ramsby S, Neumeyer JL, Grigoriadis D, Seeman P.
Abstract : The synthesis of 2-amino- and 2-halo-substituted aporphines is described. The key step is the substitution of a hydroxy group in the 2-position with an amino group effected by a Smiles rearrangement reaction of the 2-methylpropanamide derivative 6. The affinity of the new compounds for the dopamine D-2 receptor in the anterior pituitary gland was evaluated. 2-Fluoroapomorphine was the most potent compound, being 1.5 times more potent than (-)-apomorphine. The structure-activity relationships are discussed in relation to a previously proposed receptor model.
|
In vitro antagonist binding affinity was determined by displacing the [3H]-SCH- in rat striatal Dopamine receptor D1
|
None
|
238.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of the enantiomers of the dopamine autoreceptor agonist PD 135385
Year : 1993
Volume : 3
Issue : 4
First Page : 639
Last Page : 644
Authors : Jaen JC, Caprathe BW, Wise LD, Meltzer LT, Pugsley TA, Huffner TG
|
In vitro binding affinity towards rat Dopamine receptor D1 by [3H]SCH-23390 displacement.
|
None
|
432.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines as antagonists of dopamine D-1 receptors.
Year : 1990
Volume : 33
Issue : 2
First Page : 600
Last Page : 607
Authors : Schaus JM, Titus RD, Foreman MM, Mason NR, Truex LL.
Abstract : The aporphine alkaloids are a class of compounds known to possess activity at both D-1 and D-2 dopamine receptors. (R)-Apomorphine and (S)-bulbocapnine are examples of compounds which have agonist and antagonist activity, respectively, at D-1 receptors. A series of optically pure aporphines was synthesized and their activity at D-1 and D-2 dopamine receptors was studied. The (R)-aporphines uniformly had greater affinity for both D-1 and D-2 receptors than their S antipodes. Dihydroxy compound (R)-apomorphine, in accord with previous studies, was found to be a D-1 agonist. Aporphines possessing a single hydroxy group at C-11 are antagonists at the D-1 receptor. The corresponding methoxy compounds are virtually inactive at dopamine receptors. The most potent compounds, (R)-11-hydroxyaporphine (R-14) and (R)-10-bromo-11-hydroxyaporphine (R-26), are more potent than bulbocapnine as D-1 antagonists but are not as selective. A model for binding of aporphines to the D-1 receptor was formulated in which binding interactions between the receptor and the basic nitrogen and the C-11 hydroxy group of the aporphine are required for high-affinity binding to the receptor. The absolute configuration at C-6a determines the orientation of the N-6 lone pair and binding is optimal for the 6aR series. The agonist or antagonist activity of an aporphine is determined by the presence or absence, respectively, of a hydroxy group at C-10. A hydrophobic binding site may be present and may account for the high antagonist activity of (S)-bulbocapnine.
|
Inhibition of binding of [3H]SCH-23390 to Dopamine receptor D1 was determined
|
None
|
384.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties.
Year : 1990
Volume : 33
Issue : 1
First Page : 311
Last Page : 317
Authors : Jaen JC, Wise LD, Caprathe BW, Tecle H, Bergmeier S, Humblet CC, Heffner TG, Meltzer LT, Pugsley TA.
Abstract : The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.
|
Inhibition of binding of [3H]SCH-23390 to Dopamine receptor D1 in rat striatal membranes
|
None
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cis- and trans-N-benzyl-octahydrobenzo[g]quinolines. Adrenergic and dopaminergic activity studies.
Year : 2001
Volume : 11
Issue : 7
First Page : 883
Last Page : 886
Authors : Thermos K, Froudakis GE, Tagmatarchis N, Katerinopoulos HE.
Abstract : In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the dopaminergic receptors and alpha adrenoceptors. The trans N-benzyl analogues exhibited affinity at the alpha2 as well as the D1-like receptors whereas their N-unsubstituted congeners showed a distinct preference for the alpha2 adrenoceptor. Enhanced activity for the alpha2 receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.
|
In vitro effective concentration tested on HEK293 cells co-transfected with ferret Dopamine receptor D2 using FLIPR assay
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
In vitro effective concentration tested on HEK293 cells co-transfected with rat Dopamine receptor D2 using FLIPR assay
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
Ability to displace [3H]SCH-23390 binding to rat striatal Dopamine receptor D1
|
None
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : (R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1995
Volume : 38
Issue : 4
First Page : 647
Last Page : 658
Authors : Hedberg MH, Johansson AM, Nordvall G, Yliniemelä A, Li HB, Martin AR, Hjorth S, Unelius L, Sundell S, Hacksell U.
Abstract : (R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
|
Affinity of the Compound for Dopamine receptor D2 in rat striatal membrane was determined in vitro using Dopamine Antagonist [3H]-spiperone as ligand; Value ranges from (20-29)
|
None
|
24.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 4,5,6,7-tetrahydrobenzothiazole dopamine agonists display very low stereoselectivity in their interaction with dopamine receptors.
Year : 1991
Volume : 1
Issue : 4
First Page : 189
Last Page : 192
Authors : Jaen JC, Caprathe BW, Wise LD, Smith SJ, Pugsley TA, Heffner TG, Meltzer LT
|
Affinity of the Compound for Dopamine receptor D2 in rat striatal membrane was determined in vitro using Dopamine agonist [3H]N-propylnorapomorphine as ligand; Value ranges from (1.4-1.9)
|
None
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 4,5,6,7-tetrahydrobenzothiazole dopamine agonists display very low stereoselectivity in their interaction with dopamine receptors.
Year : 1991
Volume : 1
Issue : 4
First Page : 189
Last Page : 192
Authors : Jaen JC, Caprathe BW, Wise LD, Smith SJ, Pugsley TA, Heffner TG, Meltzer LT
|
Affinity for [3H]N-propylnorapomorphine (NPA) Dopamine receptor D2
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine agonist properties of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol and its enantiomers.
Year : 1990
Volume : 33
Issue : 1
First Page : 445
Last Page : 450
Authors : DeWald HA, Heffner TG, Jaen JC, Lustgarten DM, McPhail AT, Meltzer LT, Pugsley TA, Wise LD.
Abstract : The dopamine agonist profile of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined. Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labeled with the DA antagonist ligand [3H]haloperidol and moderate in vivo activity; it attenuated gamma-butyrolactone-stimulated DA synthesis, decreased DA neuronal firing of substantia nigra DA neurons, and inhibited exploratory locomotor activity in rats, a profile consistent with a DA autoreceptor agonist mechanism of action. The (+)-enantiomer 16b possessed greater DA receptor affinity with the agonist ligand [3H]-N-propylnorapomorphine than with the antagonist ligand. In rats it potently inhibited DA synthesis and neuronal firing and also inhibited exploratory locomotion. The (-)-enantiomer, on the other hand, did not have significant activity in any of these tests. This profile indicates that like many other rigid DA agonists, the dopaminergic activity resides in one enantiomer, in this case the (+)-enantiomer 16b. On the basis of single-crystal X-ray analysis of a key intermediate, the absolute configuration of 16b was found to be 4aR, 10bR.
|
Binding affinity against Dopamine receptor D2 from rat brain corpus striatum membrane
|
Rattus norvegicus
|
66.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinity of (R)-(-)-2-fluoro-N-n-propylnorapomorphine: a highly potent and selective dopamine D2 agonist.
Year : 1990
Volume : 33
Issue : 12
First Page : 3122
Last Page : 3124
Authors : Neumeyer JL, Gao YG, Kula NS, Baldessarini RJ.
|
Binding affinity at rat striatal Dopamine receptor D1 using [3H]- SCH-23390 radioligand
|
Rattus norvegicus
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues.
Year : 1990
Volume : 33
Issue : 6
First Page : 1800
Last Page : 1805
Authors : Gao YG, Baldessarini RJ, Kula NS, Neumeyer JL.
Abstract : Syntheses of (R)-(-)-2-methoxyapomorphine (R-8), its antipode S-8, and its (R)-(-)-N-n-propyl R-9 derivatives are described. The dopaminergic receptor affinities of these compounds and their 2-unsubstituted counterparts (R)-(-)-apomorphine (R(-)-APO, R-1), (S)-(+)-apomorphine (S(+)-APO, S-1), and (R)-(-)-N-n-propylnorapomorphine (R(-)-NPA, R-2), as well as those of (R)-(-)-2-chloroapomorphine (R(-)-2-Cl-APO, R-6), (R)-(-)-2-bromoapomorphine (R(-)-2-Br-APO, R-6), were determined with tissue membrane preparations of corpus striatum from rat brain. Contribution of both an N-n-propyl and a 2-hydroxy in (R)-(-)-2-hydroxy-N-n-propylnorapomorphine (R(-)-2-OH-NPA, R-7) or a methoxy group in (R)-(-)-2-methoxy-N-n-propylnorapomorphine (R(-)-2-OCH3-NPA, R-9) produced the highest D2 affinity (0.053 and 0.17 nM) and D2 over D1 selectivity (17,300 and 10,500 times) of the compounds evaluated. The structure-affinity relationships of these 2-substituted aporphines suggest that secondary binding sites of D2 receptors interact with 2-substituents on the A ring of aporphines through H-bonding.
|
Displacement of [3H]fenoldopam from Dopamine receptor D1 of rat striatum membranes
|
Rattus norvegicus
|
53.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopaminergic binding of 2-aryldopamine analogues: phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes.
Year : 1986
Volume : 29
Issue : 10
First Page : 1904
Last Page : 1912
Authors : Ladd DL, Weinstock J, Wise M, Gessner GW, Sawyer JL, Flaim KE.
Abstract : A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2 receptors. The 9-(aminomethyl)fluorenes also exhibited weak D2 binding; however, 2,5,6-trihydroxy-9H-fluorene-9-methanamine (4b) exhibited D1 binding comparable to apomorphine. The binding activity has been correlated with the calculated torsion angle of the biphenyl portion of these molecules. Good D1 dopamine binding occurs when the aromatic rings approach coplanarity; poor binding occurs when the aromatic rings are orthogonal.
|
In vitro displacement of [3H]SCH-23390 binding to rat striatal Dopamine receptor D1
|
None
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : 11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3503
Last Page : 3513
Authors : Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
|
In vitro binding affinity towards Dopamine receptor D1 by displacing [125I]FISCH radioligand in rat striatal homogenate
|
None
|
888.0
nM
|
|
Journal : J. Med. Chem.
Title : (+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine: a potential CNS D-1 dopamine receptor imaging agent.
Year : 1989
Volume : 32
Issue : 7
First Page : 1431
Last Page : 1435
Authors : Chumpradit S, Kung HF, Billings J, Kung MP, Pan S.
Abstract : Synthesis, radiolabeling, and in vitro and in vivo properties of an iodinated benzazepine, (+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3- methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, [125I]FISCH, as a potential imaging agent for evaluation of central nervous system (CNS) D-1 dopamine receptors in humans, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats (2.27, 1.40, 0.55% dose/whole brain at 2, 15, and 60 min, respectively). The striatum/cerebellum ratio was high (2.47 at 60 min after the injection). The binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 +/- 0.15 nM. Competition data (in vitro) showed the following rank order of potency: SCH-23390 greater than (+/-)-FISCH greater than (+/-)-IBZP much greater than apomorphine greater than WB 4010 greater than ketanserin approximately spiperone. The preliminary data suggest that the agent is highly selective for the CNS D-1 receptor.
|
Tested for binding affinity towards rat striatal dopamine receptor D1 using [3H]-SCH- 23390 as radioligand
|
None
|
221.0
nM
|
|
Journal : J. Med. Chem.
Title : The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
Year : 1994
Volume : 37
Issue : 21
First Page : 3523
Last Page : 3533
Authors : Wright JL, Caprathe BW, Downing DM, Glase SA, Heffner TG, Jaen JC, Johnson SJ, Kesten SR, MacKenzie RG, Meltzer LT.
Abstract : A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
|
Compound was evaluated for the inhibition of [3H]spiperone binding to Dopamine receptor D2 of rat striatal membranes
|
None
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinities of 2-(4-fluoro-3- hydroxyphenyl)ethylamine and N-substituted derivatives.
Year : 1990
Volume : 33
Issue : 9
First Page : 2408
Last Page : 2412
Authors : Claudi F, Cardellini M, Cingolani GM, Piergentili A, Peruzzi G, Balduini W.
Abstract : The synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some N,N-dialkyl derivatives (27-30) starting from 4-fluoro-3-hydroxytoluene and their in vitro binding affinities for dopamine (DA) receptor are reported. The amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26-30 were evaluated for their affinity at D-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3- hydroxyphenyl)ethylamine (30) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-1 sites. The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor.
|
In vitro binding affinity to Dopamine receptor D2 in rat striatal membranes using D2 antagonist [3H]spiperone
|
None
|
24.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and dopaminergic activity of the enantiomers of 6-methyl-4,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine (PD 128483).
Year : 1991
Volume : 1
Issue : 10
First Page : 539
Last Page : 544
Authors : Jaen JC, Caprathe BW, Wise LD, Pugsley TA, Meltzer LT, Heffner TG
|
In vitro affinity at Dopamine receptor D1 of rat striatum by [3H]SCH-23390 displacement.
|
None
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : 10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3491
Last Page : 3502
Authors : Hedberg MH, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
|
Binding Affinity was determined against Dopamine receptor D1 in rat striatal membranes using [3H]- SCH 23390 radioligand.
|
None
|
181.97
nM
|
|
Journal : J. Med. Chem.
Title : Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands.
Year : 2000
Volume : 43
Issue : 4
First Page : 599
Last Page : 608
Authors : Claudi F, Di Stefano A, Napolitani F, Cingolani GM, Giorgioni G, Fontenla JA, Montenegro GY, Rivas ME, Rosa E, Michelotto B, Orlando G, Brunetti L.
Abstract : The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3, 4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D(1)-like and D(2)-like subtypes. All compounds showed very low D(1) affinities. This could be ascribed to the absence of a catechol nucleus or of the beta-phenyldopamine pharmacophore. Only the N-methyl-5-hydroxy- (5a), N-methyl-10-hydroxy- (6a), and N-methyl-4-bromo-10-methoxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D(2) receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D(2) agonist pharmacophore: namely, the 2-(3-hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D(4) receptors, and only 5a showed low affinity for rat recombinant D(3) receptors. Analysis of the influence of Na(+) on [(3)H]spiperone binding showed that 5a displays a potential dopamine D(2) agonist profile, whereas 6a probably has a dopamine D(2) antagonist activity. The D(2) agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
|
In vitro binding affinity to Dopamine receptor D1/Dopamine receptor D2 in rat striatal membranes using [3H]N-propylnorapomorphine
|
None
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and dopaminergic activity of the enantiomers of 6-methyl-4,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine (PD 128483).
Year : 1991
Volume : 1
Issue : 10
First Page : 539
Last Page : 544
Authors : Jaen JC, Caprathe BW, Wise LD, Pugsley TA, Meltzer LT, Heffner TG
|
Equilibrium dissociation constant against recombinant Dopamine receptor D1A expressed in COS7 cells
|
Homo sapiens
|
680.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparative molecular field analysis-based prediction of drug affinities at recombinant D1A dopamine receptors.
Year : 1996
Volume : 39
Issue : 4
First Page : 850
Last Page : 859
Authors : Brusniak MY, Pearlman RS, Neve KA, Wilcox RE.
Abstract : Determination of quantitative structure-activity relationship (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K(d)) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r(2)(q(2)) value of 0.829 and a simple r(2) = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K(d) values, the q(2) value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.
|
Inhibition of [3H]N-propylnorapomorphine as radioligand for Dopamine receptor D2 in rat striatal membranes
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties.
Year : 1990
Volume : 33
Issue : 1
First Page : 311
Last Page : 317
Authors : Jaen JC, Wise LD, Caprathe BW, Tecle H, Bergmeier S, Humblet CC, Heffner TG, Meltzer LT, Pugsley TA.
Abstract : The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.
|
Inhibition of [3H]haloperidol binding for Dopamine receptor D2 in rat striatal membranes.
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties.
Year : 1990
Volume : 33
Issue : 1
First Page : 311
Last Page : 317
Authors : Jaen JC, Wise LD, Caprathe BW, Tecle H, Bergmeier S, Humblet CC, Heffner TG, Meltzer LT, Pugsley TA.
Abstract : The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.
|
Compound was tested for inhibition of [3H]spiroperidol binding against Dopamine receptor D2
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopaminergic binding of 2-aryldopamine analogues: phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes.
Year : 1986
Volume : 29
Issue : 10
First Page : 1904
Last Page : 1912
Authors : Ladd DL, Weinstock J, Wise M, Gessner GW, Sawyer JL, Flaim KE.
Abstract : A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2 receptors. The 9-(aminomethyl)fluorenes also exhibited weak D2 binding; however, 2,5,6-trihydroxy-9H-fluorene-9-methanamine (4b) exhibited D1 binding comparable to apomorphine. The binding activity has been correlated with the calculated torsion angle of the biphenyl portion of these molecules. Good D1 dopamine binding occurs when the aromatic rings approach coplanarity; poor binding occurs when the aromatic rings are orthogonal.
|
Concentration necessary to achieve half maximal inhibition of [3H](+)-23amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene binding to dopamine receptor at 1 uM
|
None
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : 2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors.
Year : 1989
Volume : 32
Issue : 3
First Page : 720
Last Page : 727
Authors : Hutchison A, Williams M, de Jesus R, Stone GA, Sylvester L, Clarke FH, Sills MA.
Abstract : Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.
|
Concentration necessary to achieve half maximal inhibition of [3H]spiperone binding dopamine receptor at 1 uM
|
None
|
182.0
nM
|
|
Journal : J. Med. Chem.
Title : 2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors.
Year : 1989
Volume : 32
Issue : 3
First Page : 720
Last Page : 727
Authors : Hutchison A, Williams M, de Jesus R, Stone GA, Sylvester L, Clarke FH, Sills MA.
Abstract : Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.
|
In vitro inhibitory activity against dopamine receptor from calf caudate using [3H]dopamine as radioligand
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine.
Year : 1985
Volume : 28
Issue : 3
First Page : 367
Last Page : 375
Authors : Nordmann R, Petcher TJ.
Abstract : A synthesis of all four diastereoisomeric 3-(tert-butoxycarbonyl)-1,6-dimethoxyoctahydrobenzo[g]quinolines 13a-d is presented. The two trans isomers 13b and 13c have been converted to tricyclic analogues 20 (CV 205-502) and 26 (205-503) of the potent dopaminomimetic ergolines CQ 32-084 and pergolide, respectively. These two compounds combine the essential moiety of apomorphine with the important 8-substituents of ergolines. Preliminary pharmacological evaluation of 20 and 26 suggests that these novel dopamine agonists combine the specificity of apomorphine with the potency, long duration of action, and good oral activity of the ergolines.
|
In vitro inhibitory activity was evaluated against [3H]dopamine (DA) calf caudate dopamine receptor
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3 alpha, 4a alpha, 10a beta)-1,2,3,4,4a,5,10,10a- -octahydro-6-hydroxy-1-propyl-3-benzo[g]quinolinyl]sulfamide.
Year : 1985
Volume : 28
Issue : 10
First Page : 1540
Last Page : 1542
Authors : Nordmann R, Widmer A.
Abstract : The synthesis and preliminary pharmacological evaluation of the optical antipodes of the title compound (+/-)-1 (CV 205-502) is presented. The dopaminomimetic activity is shown to reside entirely in the (-) enantiomer. Crystallographic analysis has proven that the absolute configuration of the active (-) enantiomer corresponds to that of its ergoline analogue 3 (CQ 32-084) and of apomorphine (5).
|
Inhibition of [3H]dopamine binding to Dopamine receptor in calf caudate nuclei.
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 8-aryltetrahydroisoquinolines as dopamine antagonists and evaluation for potential neuroleptic activity.
Year : 1980
Volume : 23
Issue : 9
First Page : 977
Last Page : 980
Authors : Ellefson CR, Prodan KA, Brougham LR, Miller A.
Abstract : The synthesis of 8-(methoxyphenyl)-1,2,3,4-tetrahydroisoquinolines using aryloxazolines as key intermediates is described. Nucleophilic displacement on an o-methoxyphenyloxazoline by an aryl Grignard reagent, followed by electrophilic substitution at the other ortho position, provided a specific route to the properly substituted benzene intermediates necessary for conversion to the tetrahydroisoquinolines. These compounds and 8-phenyl- and 2-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinolines, which are ring-opened analogues of apomorphine, were found to be dopamine antagonists by in vitro dopamine receptor studies. In vivo evaluation, however, did not substantiate potential usefulness as antipsychotic agents when they were compared with standard neuroleptic agents.
|
Inhibition of [3H]haloperidol binding to Dopamine receptor in calf caudate nuclei.
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 8-aryltetrahydroisoquinolines as dopamine antagonists and evaluation for potential neuroleptic activity.
Year : 1980
Volume : 23
Issue : 9
First Page : 977
Last Page : 980
Authors : Ellefson CR, Prodan KA, Brougham LR, Miller A.
Abstract : The synthesis of 8-(methoxyphenyl)-1,2,3,4-tetrahydroisoquinolines using aryloxazolines as key intermediates is described. Nucleophilic displacement on an o-methoxyphenyloxazoline by an aryl Grignard reagent, followed by electrophilic substitution at the other ortho position, provided a specific route to the properly substituted benzene intermediates necessary for conversion to the tetrahydroisoquinolines. These compounds and 8-phenyl- and 2-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinolines, which are ring-opened analogues of apomorphine, were found to be dopamine antagonists by in vitro dopamine receptor studies. In vivo evaluation, however, did not substantiate potential usefulness as antipsychotic agents when they were compared with standard neuroleptic agents.
|
Inhibitory binding activity against dopamine receptor using [3H]ADTN as the radioligand in striatal tissue of calf brain.
|
None
|
830.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted congeners of dopamine derived from 2-aminoindan.
Year : 1982
Volume : 25
Issue : 12
First Page : 1442
Last Page : 1446
Authors : Cannon JG, Perez JA, Bhatnagar RK, Long JP, Sharabi FM.
Abstract : Two series of N-substituted 2-aminoindan systems have been prepared: 4,5-dihydroxy-2-aminoindan (1) has a hydroxylation pattern analogous to the alpha conformer of dopamine, and 5,6-dihydroxy-2-aminoindan (2) has a hydroxylation pattern of the beta conformer of dopamine. All members of both series demonstrated only extremely weak binding to calf caudate homogenate. Certain N-alkylated 4,5-dihydroxyindans were violent emetics in the dog and were potent in blockade of the effect of stimulation of the cardioaccelerator nerve of the cat. In contrast, the 5,6-dihydroxy series displayed low or no activity/potency in these assays. Conformational analysis of the 2-aminoindan system is described and discussed.
|
Tested for binding to dopamine receptor using [3H]- ADTN as radioligand in calf caudate nucleus homogenates.
|
None
|
4.9
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.
Year : 1982
Volume : 25
Issue : 8
First Page : 990
Last Page : 992
Authors : Neumeyer JL, Arana GW, Ram VJ, Kula NS, Baldessarini RJ.
Abstract : The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine by competition with tritiated apomorphine, ADTN, and spiroperidol for binding to a membrane fraction of calf caudate nucleus, as well as for ability to stimulate adenylate cyclase. In all four tests, the rank order of potency was (-)-APO greater than (-)-THA much greater than (+)-THA. Thus, these results extend the impression that the 6aR configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and that 2-hydroxylation reduces potency in comparison with 10,11-dihydroxyaporphines.
|
Tested for binding to dopamine receptor using [3H]apomorphine as radioligand in calf caudate nucleus homogenates.
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.
Year : 1982
Volume : 25
Issue : 8
First Page : 990
Last Page : 992
Authors : Neumeyer JL, Arana GW, Ram VJ, Kula NS, Baldessarini RJ.
Abstract : The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine by competition with tritiated apomorphine, ADTN, and spiroperidol for binding to a membrane fraction of calf caudate nucleus, as well as for ability to stimulate adenylate cyclase. In all four tests, the rank order of potency was (-)-APO greater than (-)-THA much greater than (+)-THA. Thus, these results extend the impression that the 6aR configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and that 2-hydroxylation reduces potency in comparison with 10,11-dihydroxyaporphines.
|
Tested for binding to dopamine receptor using [3H]spiroperidol as radioligand in calf caudate nucleus homogenates.
|
None
|
8.6
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines. 39. Synthesis, dopamine receptor binding, and pharmacological activity of (R)-(-)- and (S)-(+)-2-hydroxyapomorphine.
Year : 1982
Volume : 25
Issue : 8
First Page : 990
Last Page : 992
Authors : Neumeyer JL, Arana GW, Ram VJ, Kula NS, Baldessarini RJ.
Abstract : The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically in vitro in comparison with (-)-apomorphine [(-)-APO] and dopamine by competition with tritiated apomorphine, ADTN, and spiroperidol for binding to a membrane fraction of calf caudate nucleus, as well as for ability to stimulate adenylate cyclase. In all four tests, the rank order of potency was (-)-APO greater than (-)-THA much greater than (+)-THA. Thus, these results extend the impression that the 6aR configuration for hydroxyaporphines is preferred for interactions with putative dopamine receptors and that 2-hydroxylation reduces potency in comparison with 10,11-dihydroxyaporphines.
|
Agonistic activity against calf striatal Dopamine receptor using [3H]- ADTN radioligand
|
Bos taurus
|
3.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues.
Year : 1990
Volume : 33
Issue : 6
First Page : 1800
Last Page : 1805
Authors : Gao YG, Baldessarini RJ, Kula NS, Neumeyer JL.
Abstract : Syntheses of (R)-(-)-2-methoxyapomorphine (R-8), its antipode S-8, and its (R)-(-)-N-n-propyl R-9 derivatives are described. The dopaminergic receptor affinities of these compounds and their 2-unsubstituted counterparts (R)-(-)-apomorphine (R(-)-APO, R-1), (S)-(+)-apomorphine (S(+)-APO, S-1), and (R)-(-)-N-n-propylnorapomorphine (R(-)-NPA, R-2), as well as those of (R)-(-)-2-chloroapomorphine (R(-)-2-Cl-APO, R-6), (R)-(-)-2-bromoapomorphine (R(-)-2-Br-APO, R-6), were determined with tissue membrane preparations of corpus striatum from rat brain. Contribution of both an N-n-propyl and a 2-hydroxy in (R)-(-)-2-hydroxy-N-n-propylnorapomorphine (R(-)-2-OH-NPA, R-7) or a methoxy group in (R)-(-)-2-methoxy-N-n-propylnorapomorphine (R(-)-2-OCH3-NPA, R-9) produced the highest D2 affinity (0.053 and 0.17 nM) and D2 over D1 selectivity (17,300 and 10,500 times) of the compounds evaluated. The structure-affinity relationships of these 2-substituted aporphines suggest that secondary binding sites of D2 receptors interact with 2-substituents on the A ring of aporphines through H-bonding.
|
The IC50 value was reported as apparent, since [3H]NCA was purported to be irreversible. Result indicates the mean of two separate experiments, each performed in triplicate.
|
Canis lupus familiaris
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines. 58. N-(2-chloroethyl) [8,9-2H]norapomorphine, an irreversible ligand for dopamine receptors: synthesis and application.
Year : 1984
Volume : 27
Issue : 6
First Page : 806
Last Page : 810
Authors : Guan JH, Neumeyer JL, Filer CN, Ahern DG, Lilly L, Watanabe M, Grigoriadis D, Seeman P.
Abstract : The synthesis of the title compounds (1c and its 2H isomer 1b) from N-(2-hydroxyethyl)norapomorphine was carried out by ring bromination, followed by chlorination to the 2-chloroethyl compound 6. Further reduction with 2H2 or 3H2 and Pd/C gave 1b or 1c. Radiochemically pure (97%) 1c was obtained with a specific activity of 16.3 Ci/mmol. The purity of 1c was determined by LC, HPLC, UV, and NMR. [3H]NCA was shown to label the D2 receptor; however, the D2 signal appears to be only a small portion of the total signal, which may include binding to other dopamine receptor subtypes (D1 and D3).
|
Dopaminergic activity assessed in vitro for displacement of [3H]apomorphine from specific binding sites on rat striatal membranes
|
None
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.
Year : 1984
Volume : 27
Issue : 12
First Page : 1607
Last Page : 1613
Authors : Jones JH, Anderson PS, Baldwin JJ, Clineschmidt BV, McClure DE, Lundell GF, Randall WC, Martin GE, Williams M, Hirshfield JM.
Abstract : A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.
|
Compound was tested for inhibitory binding activity against dopamine receptor in rat striatal membranes using [3H]HAL as the radioligand.
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones.
Year : 1991
Volume : 34
Issue : 1
First Page : 248
Last Page : 256
Authors : Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT.
Abstract : The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.
|
In vitro effective concentration tested on HEK293 cells co-transfected with human Dopamine receptor D2 using FLIPR assay
|
None
|
5.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
In vitro affinity to dopamine receptor using [3H]HPD as radioligand in rat striatal membranes
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : 6- and 8-hydroxy-3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans. Dopamine agonists with autoreceptor selectivity.
Year : 1988
Volume : 31
Issue : 3
First Page : 688
Last Page : 691
Authors : Wise LD, DeWald HA, Hawkins ES, Reynolds DM, Heffner TG, Meltzer LT, Pugsley TA.
Abstract : The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.
|
In vitro affinity to dopamine receptor using [3H]NPAD as radioligand in rat striatal membranes
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : 6- and 8-hydroxy-3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans. Dopamine agonists with autoreceptor selectivity.
Year : 1988
Volume : 31
Issue : 3
First Page : 688
Last Page : 691
Authors : Wise LD, DeWald HA, Hawkins ES, Reynolds DM, Heffner TG, Meltzer LT, Pugsley TA.
Abstract : The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.
|
In vitro inhibition of [3H]haloperidol (HPD) binding to dopamine (DA) receptor of rat striatal membranes
|
Rattus norvegicus
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines.
Year : 1988
Volume : 31
Issue : 8
First Page : 1621
Last Page : 1625
Authors : Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT.
Abstract : The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties are described. One of these compounds, 3-[3-(4-phenyl-1-piperazinyl)propoxy]benzenamine (4c), has been identified as a selective dopamine (DA) autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. In addition, 4c possesses good oral activity in the Sidman conditioned avoidance test in squirrel monkeys, which is indicative of antipsychotic activity. In a primate model, 4c was found to lack the liability for extrapyramidal side effects usually associated with antipsychotic drugs.
|
Inhibitory concentration against [3H]- spiperone binding to Dopamine receptor at 10 mg/kg
|
Rattus norvegicus
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine.
Year : 1987
Volume : 30
Issue : 3
First Page : 494
Last Page : 498
Authors : Schneider CS, Mierau J.
Abstract : The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor agonist activities of the compounds were evaluated. Testing revealed (-)-5, the S enantiomer, to be the most active compound tested (inhibition of GBL accelerated dopamine synthesis and inhibition of alpha-methyltyrosine-induced decline of DA). In addition (-)-5 does not exhibit stereotyped behavior, suggesting a pronounced selectivity for DA autoreceptors.
|
In vitro effective concentration tested on HEK293 cells co-transfected with ferret Dopamine receptor D4 using FLIPR assay
|
None
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
Binding Affinity was determined against Dopamine receptor D2 in rat striatal membranes using [3H]- spiperone radioligand.
|
None
|
54.95
nM
|
|
Journal : J. Med. Chem.
Title : Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands.
Year : 2000
Volume : 43
Issue : 4
First Page : 599
Last Page : 608
Authors : Claudi F, Di Stefano A, Napolitani F, Cingolani GM, Giorgioni G, Fontenla JA, Montenegro GY, Rivas ME, Rosa E, Michelotto B, Orlando G, Brunetti L.
Abstract : The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3, 4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D(1)-like and D(2)-like subtypes. All compounds showed very low D(1) affinities. This could be ascribed to the absence of a catechol nucleus or of the beta-phenyldopamine pharmacophore. Only the N-methyl-5-hydroxy- (5a), N-methyl-10-hydroxy- (6a), and N-methyl-4-bromo-10-methoxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D(2) receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D(2) agonist pharmacophore: namely, the 2-(3-hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D(4) receptors, and only 5a showed low affinity for rat recombinant D(3) receptors. Analysis of the influence of Na(+) on [(3)H]spiperone binding showed that 5a displays a potential dopamine D(2) agonist profile, whereas 6a probably has a dopamine D(2) antagonist activity. The D(2) agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
|
In vitro effective concentration tested on HEK293 cells co-transfected with rat Dopamine receptor D4 using FLIPR assay
|
None
|
5.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
Compound was evaluated for the binding affinity against [3H]U-86,170-labeled D2 sites in cloned CHO cells
|
None
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.
Year : 1993
Volume : 36
Issue : 8
First Page : 1053
Last Page : 1068
Authors : Lin CH, Haadsma-Svensson SR, Lahti RA, McCall RB, Piercey MF, Schreur PJ, Von Voigtlander PF, Smith MW, Chidester CG.
Abstract : The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.
|
Compound was evaluated for the binding affinity against [3H]U-86,170-labeled D2 sites in cloned CHO cells
|
None
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives.
Year : 1993
Volume : 36
Issue : 8
First Page : 1069
Last Page : 1083
Authors : Lin CH, Haadsma-Svensson SR, Phillips G, Lahti RA, McCall RB, Piercey MF, Schreur PJ, Von Voigtlander PF, Smith MW, Chidester CG.
Abstract : The conformationally restricted linear tricyclic analogs of 5- and 8-hydroxy-2-(di-n-propylamino)-tetralins were investigated for their serotonergic and dopaminergic properties. These cis and trans analogs of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (3), where a five-membered ring is fused between the nitrogen and C-3 carbon of 2-aminotetralin, were synthesized from 5-methoxy- and 8-methoxytetralones. The enantiomers of trans-5-methoxy-N-n-propyl and -N-allyl analogs were obtained via fractional recrystallization of their di-p-toluoyl-L (or D) tartaric acid salts. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. In the 5-substituted series (R1 in 3), the trans isomers were found to possess higher levels of pharmacological activity then the corresponding cis isomers. The trans-5-methoxy analogs showed selective 5-HT1A receptor activity in vitro but displayed mixed 5-HT1A and D2 agonist properties in vivo. The corresponding trans-5-hydroxy analogs were found to be potent D2 agonists with full intrinsic activity. An examination of nitrogen substitution (R2 in 3) revealed that analogs with either an allyl or an n-propyl group displayed equipotent activities. Substitution with a cyclopropylmethyl or benzyl group resulted in reduced activity. Among the resolved analogs tested, the activity was found to reside exclusively in the (3aS)-(-)-enantiomers. In the 8-substituted series (R1 in 3), only 8-methoxy-N-allyl analogs were synthesized and evaluated. In this case, both cis and trans isomers showed equally weak in vitro 5-HT1A receptor agonist activity devoid of dopaminergic effects. The presence of an additional methyl group at the C-2 position (R3 in 3) of the cis-(+/-)-8-methoxy-N-n-propyl analog resulted in enhancement of in vitro 5-HT1A receptor binding affinity, with the (2 beta,3a alpha,9a alpha)-(+/-)-isomer displaying potency 35 times greater than the (2 alpha,3a alpha,9a alpha)-(+/-)-isomer.
|
Tested for binding affinity towards human D2L receptor using [3H]spiperone as radioligand
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
Year : 1994
Volume : 37
Issue : 21
First Page : 3523
Last Page : 3533
Authors : Wright JL, Caprathe BW, Downing DM, Glase SA, Heffner TG, Jaen JC, Johnson SJ, Kesten SR, MacKenzie RG, Meltzer LT.
Abstract : A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
|
Compound was tested in vitro for binding affinity towards Dopamine receptor D2 in rat striatal membrane by using [3H]spiperone as radioligand
|
None
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 3.6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine.
Year : 1991
Volume : 34
Issue : 9
First Page : 2736
Last Page : 2746
Authors : Caprathe BW, Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT, Parvez M.
Abstract : A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
|
Concentration inhibiting specific binding of [3H]haloperidol to Dopamine receptor D2 from rat striatal brain.
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine agonist properties of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol and its enantiomers.
Year : 1990
Volume : 33
Issue : 1
First Page : 445
Last Page : 450
Authors : DeWald HA, Heffner TG, Jaen JC, Lustgarten DM, McPhail AT, Meltzer LT, Pugsley TA, Wise LD.
Abstract : The dopamine agonist profile of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined. Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labeled with the DA antagonist ligand [3H]haloperidol and moderate in vivo activity; it attenuated gamma-butyrolactone-stimulated DA synthesis, decreased DA neuronal firing of substantia nigra DA neurons, and inhibited exploratory locomotor activity in rats, a profile consistent with a DA autoreceptor agonist mechanism of action. The (+)-enantiomer 16b possessed greater DA receptor affinity with the agonist ligand [3H]-N-propylnorapomorphine than with the antagonist ligand. In rats it potently inhibited DA synthesis and neuronal firing and also inhibited exploratory locomotion. The (-)-enantiomer, on the other hand, did not have significant activity in any of these tests. This profile indicates that like many other rigid DA agonists, the dopaminergic activity resides in one enantiomer, in this case the (+)-enantiomer 16b. On the basis of single-crystal X-ray analysis of a key intermediate, the absolute configuration of 16b was found to be 4aR, 10bR.
|
Evaluated for the affinity against Dopamine receptor D2 in rat striatal membranes
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Preparation of 7-oxaaporphine derivatives and evaluation of their dopaminergic activity.
Year : 1988
Volume : 31
Issue : 7
First Page : 1466
Last Page : 1471
Authors : Banzatti C, Carfagna N, Commisso R, Heidempergher F, Pegrassi L, Melloni P.
Abstract : A series of 7-oxaaporphine derivatives was prepared. The compounds were evaluated as dopaminergic agents. None of them showed either affinity for dopamine receptors or activity in vivo in the climbing behavior (mice) and turning behavior (6-hydroxydopamine-lesioned rats) tests. The lack of activity is tentatively related to the effect of the oxygen atom on the pKa of these molecules.
|
In vitro agonist binding affinity was determined by displacing the [3H]N-propylnorapomorphine ([3H]NPA) in rat striatal Dopamine receptor D2
|
None
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of the enantiomers of the dopamine autoreceptor agonist PD 135385
Year : 1993
Volume : 3
Issue : 4
First Page : 639
Last Page : 644
Authors : Jaen JC, Caprathe BW, Wise LD, Meltzer LT, Pugsley TA, Huffner TG
|
Displacement of [3H]spiperone from rat striatal Dopamine receptor D2
|
Rattus norvegicus
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of the enantiomers of the dopamine autoreceptor agonist PD 135385
Year : 1993
Volume : 3
Issue : 4
First Page : 639
Last Page : 644
Authors : Jaen JC, Caprathe BW, Wise LD, Meltzer LT, Pugsley TA, Huffner TG
|
Ability to displace [3H]raclopride binding to cloned human Dopamine receptor D2A
|
None
|
41.9
nM
|
|
Journal : J. Med. Chem.
Title : (R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1995
Volume : 38
Issue : 4
First Page : 647
Last Page : 658
Authors : Hedberg MH, Johansson AM, Nordvall G, Yliniemelä A, Li HB, Martin AR, Hjorth S, Unelius L, Sundell S, Hacksell U.
Abstract : (R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
|
Displacement of [3H]raclopride from human Dopamine receptor D2A
|
Homo sapiens
|
41.9
nM
|
|
Journal : J. Med. Chem.
Title : 11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3503
Last Page : 3513
Authors : Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
|
In vitro binding affinity towards cloned human Dopamine receptor D2A using [3H]- Raclopride as radioligand.
|
None
|
41.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Serotonergic and dopaminergic activities of rigidified (R)-aporphine derivatives.
Year : 2001
Volume : 11
Issue : 3
First Page : 367
Last Page : 370
Authors : Linnanen T, Brisander M, Mohell N, Johansson AM.
Abstract : Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.
|
In vitro affinity at human cloned Dopamine receptor D2A by [3H]-raclopride displacement.
|
None
|
41.9
nM
|
|
Journal : J. Med. Chem.
Title : 10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.
Year : 1996
Volume : 39
Issue : 18
First Page : 3491
Last Page : 3502
Authors : Hedberg MH, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM.
Abstract : Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
|
Equilibrium dissociation constant against recombinant Dopamine receptor D2A expressed in COS7 cells
|
None
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparative molecular field analysis-based prediction of drug affinities at recombinant D1A dopamine receptors.
Year : 1996
Volume : 39
Issue : 4
First Page : 850
Last Page : 859
Authors : Brusniak MY, Pearlman RS, Neve KA, Wilcox RE.
Abstract : Determination of quantitative structure-activity relationship (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K(d)) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r(2)(q(2)) value of 0.829 and a simple r(2) = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K(d) values, the q(2) value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.
|
In vitro binding affinity towards rat Dopamine receptor D2 by [3H]spiperone displacement.
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Aporphines as antagonists of dopamine D-1 receptors.
Year : 1990
Volume : 33
Issue : 2
First Page : 600
Last Page : 607
Authors : Schaus JM, Titus RD, Foreman MM, Mason NR, Truex LL.
Abstract : The aporphine alkaloids are a class of compounds known to possess activity at both D-1 and D-2 dopamine receptors. (R)-Apomorphine and (S)-bulbocapnine are examples of compounds which have agonist and antagonist activity, respectively, at D-1 receptors. A series of optically pure aporphines was synthesized and their activity at D-1 and D-2 dopamine receptors was studied. The (R)-aporphines uniformly had greater affinity for both D-1 and D-2 receptors than their S antipodes. Dihydroxy compound (R)-apomorphine, in accord with previous studies, was found to be a D-1 agonist. Aporphines possessing a single hydroxy group at C-11 are antagonists at the D-1 receptor. The corresponding methoxy compounds are virtually inactive at dopamine receptors. The most potent compounds, (R)-11-hydroxyaporphine (R-14) and (R)-10-bromo-11-hydroxyaporphine (R-26), are more potent than bulbocapnine as D-1 antagonists but are not as selective. A model for binding of aporphines to the D-1 receptor was formulated in which binding interactions between the receptor and the basic nitrogen and the C-11 hydroxy group of the aporphine are required for high-affinity binding to the receptor. The absolute configuration at C-6a determines the orientation of the N-6 lone pair and binding is optimal for the 6aR series. The agonist or antagonist activity of an aporphine is determined by the presence or absence, respectively, of a hydroxy group at C-10. A hydrophobic binding site may be present and may account for the high antagonist activity of (S)-bulbocapnine.
|
Inhibition of binding of [3H]spiroperidol to Dopamine receptor D2 in rat striatal membranes
|
None
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cis- and trans-N-benzyl-octahydrobenzo[g]quinolines. Adrenergic and dopaminergic activity studies.
Year : 2001
Volume : 11
Issue : 7
First Page : 883
Last Page : 886
Authors : Thermos K, Froudakis GE, Tagmatarchis N, Katerinopoulos HE.
Abstract : In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the dopaminergic receptors and alpha adrenoceptors. The trans N-benzyl analogues exhibited affinity at the alpha2 as well as the D1-like receptors whereas their N-unsubstituted congeners showed a distinct preference for the alpha2 adrenoceptor. Enhanced activity for the alpha2 receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.
|
Inhibitory concentration against radioligand [3H](-)-sulpiride binding to Dopamine receptor D2 in rat
|
None
|
5.1
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs.
Year : 1999
Volume : 42
Issue : 6
First Page : 1076
Last Page : 1087
Authors : Nakazato A, Ohta K, Sekiguchi Y, Okuyama S, Chaki S, Kawashima Y, Hatayama K.
Abstract : sigma Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for sigma receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N, N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for sigma receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.
|
Neuroleptic activity in terms of [3H]spiroperidol binding in rat striatal membrane to Dopamine receptor D2
|
None
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.
Year : 1991
Volume : 34
Issue : 1
First Page : 194
Last Page : 197
Authors : Iorio MA, Frigeni V, Bowman ER, Harris LS, May EL, Aceto MD.
Abstract : The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.
|
In vitro affinity at mutant D2 receptor (S197A) in C6 (glioma) cell membranes.
|
None
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA-based prediction of agonist affinities at recombinant wild type versus serine to alanine point mutated D2 dopamine receptors.
Year : 2000
Volume : 43
Issue : 16
First Page : 3005
Last Page : 3019
Authors : Wilcox RE, Huang WH, Brusniak MY, Wilcox DM, Pearlman RS, Teeter MM, DuRand CJ, Wiens BL, Neve KA.
Abstract : Agonist affinity changes dramatically as a result of serine to alanine mutations (S193A, S194A, and S197A) within the fifth transmembrane region of D2 dopamine receptors and other receptors for monoamine neurotransmitters. However, agonist 2D-structure does not predict which drugs will be sensitive to which point mutations. Modeling drug-receptor interactions at the 3D level offers considerably more promise in this regard. In particular, a comparison of the same test set of agonists across receptors differing minimally (point mutations) offers promise to enhance the understanding of the structural bases for drug-receptor interactions. We have previously shown that comparative molecular field analysis (CoMFA) can be applied to comparisons of affinity at recombinant D1 and D2 dopamine receptors for the same set of agonists, a differential QSAR. Here, we predicted agonist K(L) for the same set of agonists at wild type D2 vs S193A, S194A, and S197A receptors using CoMFA. Each model used bromocriptine as the template. ln(1/K(L)) values for the low-affinity agonist binding conformation at recombinant wild type and mutant D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA of the 16 aligned agonist structures. The resulting CoMFA models yielded cross-validated R(2) (q(2)) values ranging from 0.835 to 0.864 and simple R(2) values ranging from 0.999 to 1.000. Predictions of test compound affinities at WT and each mutant receptor were close to measured affinity values. This finding confirmed the predictive ability of the models and their differences from one another. The results strongly support the idea that CoMFA models of the same training set of compounds applied to WT vs mutant receptors can accurately predict differences in drug affinity at each. Furthermore, in a "proof of principle", two different templates were used to derive the CoMFA model for the WT and S193A mutant receptors. Pergolide was chosen as an alternate template because it showed a significant increase in affinity as a result of the S193A mutation. In this instance both the bromocriptine- and pergolide-based CoMFA models were similar to one another but different from those for the WT receptor using bromocriptine- or pergolide- as templates. The pergolide-based S193A model was more strikingly different from that of the WT receptor than was the bromocriptine-based S193A model. This suggests that a "dual-template" approach to differential CoMFA may have special value in elucidating key differences across related receptor types and in determining important elements of the drug-receptor interaction.
|
In vitro affinity at wild type Dopamine receptor D2 on C6 (glioma) cell membranes.
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA-based prediction of agonist affinities at recombinant wild type versus serine to alanine point mutated D2 dopamine receptors.
Year : 2000
Volume : 43
Issue : 16
First Page : 3005
Last Page : 3019
Authors : Wilcox RE, Huang WH, Brusniak MY, Wilcox DM, Pearlman RS, Teeter MM, DuRand CJ, Wiens BL, Neve KA.
Abstract : Agonist affinity changes dramatically as a result of serine to alanine mutations (S193A, S194A, and S197A) within the fifth transmembrane region of D2 dopamine receptors and other receptors for monoamine neurotransmitters. However, agonist 2D-structure does not predict which drugs will be sensitive to which point mutations. Modeling drug-receptor interactions at the 3D level offers considerably more promise in this regard. In particular, a comparison of the same test set of agonists across receptors differing minimally (point mutations) offers promise to enhance the understanding of the structural bases for drug-receptor interactions. We have previously shown that comparative molecular field analysis (CoMFA) can be applied to comparisons of affinity at recombinant D1 and D2 dopamine receptors for the same set of agonists, a differential QSAR. Here, we predicted agonist K(L) for the same set of agonists at wild type D2 vs S193A, S194A, and S197A receptors using CoMFA. Each model used bromocriptine as the template. ln(1/K(L)) values for the low-affinity agonist binding conformation at recombinant wild type and mutant D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA of the 16 aligned agonist structures. The resulting CoMFA models yielded cross-validated R(2) (q(2)) values ranging from 0.835 to 0.864 and simple R(2) values ranging from 0.999 to 1.000. Predictions of test compound affinities at WT and each mutant receptor were close to measured affinity values. This finding confirmed the predictive ability of the models and their differences from one another. The results strongly support the idea that CoMFA models of the same training set of compounds applied to WT vs mutant receptors can accurately predict differences in drug affinity at each. Furthermore, in a "proof of principle", two different templates were used to derive the CoMFA model for the WT and S193A mutant receptors. Pergolide was chosen as an alternate template because it showed a significant increase in affinity as a result of the S193A mutation. In this instance both the bromocriptine- and pergolide-based CoMFA models were similar to one another but different from those for the WT receptor using bromocriptine- or pergolide- as templates. The pergolide-based S193A model was more strikingly different from that of the WT receptor than was the bromocriptine-based S193A model. This suggests that a "dual-template" approach to differential CoMFA may have special value in elucidating key differences across related receptor types and in determining important elements of the drug-receptor interaction.
|
Binding affinity at rat striatal Dopamine receptor D2 using [3H]- piperone radioligand
|
Rattus norvegicus
|
11.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues.
Year : 1990
Volume : 33
Issue : 6
First Page : 1800
Last Page : 1805
Authors : Gao YG, Baldessarini RJ, Kula NS, Neumeyer JL.
Abstract : Syntheses of (R)-(-)-2-methoxyapomorphine (R-8), its antipode S-8, and its (R)-(-)-N-n-propyl R-9 derivatives are described. The dopaminergic receptor affinities of these compounds and their 2-unsubstituted counterparts (R)-(-)-apomorphine (R(-)-APO, R-1), (S)-(+)-apomorphine (S(+)-APO, S-1), and (R)-(-)-N-n-propylnorapomorphine (R(-)-NPA, R-2), as well as those of (R)-(-)-2-chloroapomorphine (R(-)-2-Cl-APO, R-6), (R)-(-)-2-bromoapomorphine (R(-)-2-Br-APO, R-6), were determined with tissue membrane preparations of corpus striatum from rat brain. Contribution of both an N-n-propyl and a 2-hydroxy in (R)-(-)-2-hydroxy-N-n-propylnorapomorphine (R(-)-2-OH-NPA, R-7) or a methoxy group in (R)-(-)-2-methoxy-N-n-propylnorapomorphine (R(-)-2-OCH3-NPA, R-9) produced the highest D2 affinity (0.053 and 0.17 nM) and D2 over D1 selectivity (17,300 and 10,500 times) of the compounds evaluated. The structure-affinity relationships of these 2-substituted aporphines suggest that secondary binding sites of D2 receptors interact with 2-substituents on the A ring of aporphines through H-bonding.
|
Ability to displace [3H]raclopride from dopamine receptor D2 in rat striatal homogenates.
|
None
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.
Year : 1992
Volume : 35
Issue : 6
First Page : 1076
Last Page : 1092
Authors : Moon MW, Morris JK, Heier RF, Chidester CG, Hoffmann WE, Piercey MF, Althaus JS, Von Voigtlander PF, Evans DL, Figur LM.
Abstract : The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
|
Tested for binding affinity towards human D3 receptor using [3H]spiperone as radioligand
|
None
|
7.8
nM
|
|
Journal : J. Med. Chem.
Title : The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
Year : 1994
Volume : 37
Issue : 21
First Page : 3523
Last Page : 3533
Authors : Wright JL, Caprathe BW, Downing DM, Glase SA, Heffner TG, Jaen JC, Johnson SJ, Kesten SR, MacKenzie RG, Meltzer LT.
Abstract : A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
|
Displacement of [3H]raclopride from human dopamine receptor D2A expressed in mouse Ltk cells
|
Homo sapiens
|
41.9
nM
|
|
Journal : J. Med. Chem.
Title : Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: selective serotonin 5-HT(7) receptor antagonists.
Year : 2001
Volume : 44
Issue : 9
First Page : 1337
Last Page : 1340
Authors : Linnanen T, Brisander M, Unelius L, Rosqvist S, Nordvall G, Hacksell U, Johansson AM.
|
Tested for affinity against cloned mammalian dopamine autoreceptor (DA) D2 receptors expressed in CHO-K1 cells using [3H]spiperone as radioligand
|
None
|
217.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships.
Year : 1994
Volume : 37
Issue : 17
First Page : 2735
Last Page : 2753
Authors : Sonesson C, Lin CH, Hansson L, Waters N, Svensson K, Carlsson A, Smith MW, Wikström H.
Abstract : A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.
|
Tested for binding affinity towards rat striatal D2 receptor using [3H]NPA as radioligand
|
None
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
Year : 1994
Volume : 37
Issue : 21
First Page : 3523
Last Page : 3533
Authors : Wright JL, Caprathe BW, Downing DM, Glase SA, Heffner TG, Jaen JC, Johnson SJ, Kesten SR, MacKenzie RG, Meltzer LT.
Abstract : A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
|
Tested for binding affinity towards rat striatal D2 receptor using [3H]spiperone as radioligand
|
None
|
17.3
nM
|
|
Journal : J. Med. Chem.
Title : The discovery and structure-activity relationships of 1,2,3,6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents.
Year : 1994
Volume : 37
Issue : 21
First Page : 3523
Last Page : 3533
Authors : Wright JL, Caprathe BW, Downing DM, Glase SA, Heffner TG, Jaen JC, Johnson SJ, Kesten SR, MacKenzie RG, Meltzer LT.
Abstract : A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine (14), was identified. The structure-activity relationships surrounding this compound were studied by synthesis of analogues and evaluation of their dopaminergic activity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridine to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrahydro-4-phenylpyridine could be replaced by other aryl-cyclic amines with a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better tolerated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate salts. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crystal structure determination of an intermediate identified the (+)-isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidance test in squirrel monkeys with an ED50 of 0.6 mg/kg. The overall profile suggests that (R)-(+)-14 may be a clinically useful antipsychotic agent.
|
In vitro effective concentration tested on HEK293 cells co-transfected with human Dopamine receptor D4 using FLIPR assay
|
None
|
4.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
Year : 2004
Volume : 47
Issue : 15
First Page : 3853
Last Page : 3864
Authors : Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO.
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
|
Ability to inhibit the specific binding of [3H]- dihydromorphine to opiate receptors in rat brain membrane preparation by 50%
|
None
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Combined analgesic/neuroleptic activity in N-butyrophenone prodine-like compounds.
Year : 1987
Volume : 30
Issue : 10
First Page : 1906
Last Page : 1910
Authors : Iorio MA, Reymer TP, Frigeni V.
Abstract : Some 4-phenyl-4-piperidinols, corresponding esters, and related compounds with a p-fluorobutyrophenone chain on nitrogen were synthesized and evaluated in in vitro and in vivo tests in order to examine their ability to interact contemporaneously with opioid and dopamine receptors. The propionyloxy derivatives showed a good combination of analgesic and neuroleptic activity. With a 3-methyl substituent on the piperidine ring, the beta-configuration was the more active form not only for analgesic activity, as expected from previous results on prodines, but also for neuroleptic activity. Haloperidol and its propionate were also tested as reference compounds.
|
Inhibition of the constrictor response to electrical stimulation in rabbit ear artery.
|
Oryctolagus cuniculus
|
44.0
nM
|
|
Journal : J. Med. Chem.
Title : Dopamine receptor agonists: 3-allyl-6-chloro-2,3,4,5-tetrahydro- 1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol and a series of related 3-benzazepines.
Year : 1986
Volume : 29
Issue : 5
First Page : 733
Last Page : 740
Authors : Ross ST, Franz RG, Wilson JW, Brenner M, DeMarinis RM, Hieble JP, Sarau HM.
Abstract : The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-dio l (SK&F 82526) not only retains the exceptional D-1 agonist potency of its parent but also displays reasonably potent D-2 agonist activity, as measured by a dopamine-sensitive adenylate cyclase test and a rabbit ear artery assay, respectively. Several additional N-substituted compounds were prepared to explore the D-2/D-1 agonist relationship. The N-methyl analogue retained good D-2 agonist potency, but this substitution converted D-1 agonist activity into antagonist activity. Most other N-substituents sharply decreased D-2 agonist potency including the N-n-propyl group. This observation was surprising since the introduction of mono- or di-N-n-propyl substituent(s) is commonly linked with retention or enhancement of D-2 agonist potency in other series of dopamine agonists. The N-(2-hydroxyethyl) analogue retains about one-fourth the D-2 potency of SK&F 85174. Several synthetic methods were used to prepare these compounds. N-Allylation of a trimethoxybenzazepine followed by cleavage of the methyl ethers with boron tribromide was the preferred method. Other methods used were direct alkylation of the trihydroxy secondary amine, i.e., SK&F 82526, and an acylation-amide reduction-cleavage method.
|
Concentration required to reduce the specific binding of [3H]NPA by 50% to rat corpus striatum
|
Rattus norvegicus
|
22.6
nM
|
|
Journal : J. Med. Chem.
Title : 6,7-Dihydroxy-3-chromanamine: synthesis and pharmacological activity of an oxygen isostere of the dopamine agonist 6,7-dihydroxy-2-aminotetralin.
Year : 1984
Volume : 27
Issue : 10
First Page : 1340
Last Page : 1343
Authors : Horn AS, Kaptein B, Mulder TB, de Vries JB, Wynberg H.
Abstract : 6,7-Dihydroxy-3-chromanamine, the oxygen isostere of 6,7-dihydroxy-2-aminotetralin (6,7-ADTN), has been synthesized and its dopaminergic activity in various test systems determined. Following bilateral injection into the rat nucleus accumbens, a pattern of locomotor activity similar to that produced by 6,7-ADTN was observed. Its ability to displace N-n-propyl[3H]norapomorphine binding to homogenates of rat brain corpus striatum was found to be about 15 times weaker than 6,7-ADTN and apomorphine. Like 6,7-ADTN it failed to influence dopamine metabolism following an intraperitoneal injection. It is suggested that in addition to the 2-aminotetralins, the 3-chromanamines may be a potential source of new dopamine receptor agonists.
|
Compound was evaluated for inhibition of binding of [3H]dopamine to rat caudate tissue.
|
Rattus norvegicus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted congeners of dopamine derived from octahydrobenzo[g]quinoline and octahydrobenzo[f]quinoline.
Year : 1984
Volume : 27
Issue : 2
First Page : 190
Last Page : 195
Authors : Cannon JG, Hamer RL, Ilhan M, Bhatnagar RK, Long JP.
Abstract : Series of N-alkylated derivatives of trans-octahydrobenzo[g]quinoline and of cis- and trans-octahydrobenzo[f]quinoline were prepared for pharmacological testing as congeners of 2-amino-5,7-dihydroxytetralin, which elicits dopaminergic effects in a variety of assays. Trans-fused compounds bearing N-ethyl or N-n-propyl displayed high potency/activity in inhibition of effect of stimulation of the cat cardioaccelerator nerve. Certain N-alkyl homologues in the octahydrobenzo[f]quinoline series showed high potency in binding studies in rat caudate homogenate.
|
Inhibition of dopamine neuronal firing in the anesthetized rats after ip administration at a dose 2.5 mg/kg
|
Rattus norvegicus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines.
Year : 1988
Volume : 31
Issue : 8
First Page : 1621
Last Page : 1625
Authors : Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT.
Abstract : The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties are described. One of these compounds, 3-[3-(4-phenyl-1-piperazinyl)propoxy]benzenamine (4c), has been identified as a selective dopamine (DA) autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. In addition, 4c possesses good oral activity in the Sidman conditioned avoidance test in squirrel monkeys, which is indicative of antipsychotic activity. In a primate model, 4c was found to lack the liability for extrapyramidal side effects usually associated with antipsychotic drugs.
|
Compound tested for % inhibition of DA neuronal firing at an intraperitoneal dose of 2.5 mg/kg.
|
Rattus norvegicus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones.
Year : 1991
Volume : 34
Issue : 1
First Page : 248
Last Page : 256
Authors : Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT.
Abstract : The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.
|
Tested for inhibition of dopamine neuronal firing in rat at the dose of 0.25 mg/Kg by intraperitoneal administration
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of the enantiomers of the dopamine autoreceptor agonist PD 135385
Year : 1993
Volume : 3
Issue : 4
First Page : 639
Last Page : 644
Authors : Jaen JC, Caprathe BW, Wise LD, Meltzer LT, Pugsley TA, Huffner TG
|
Percent inhibition of spontaneous DA neuronal firing in the substantia nigra of anesthetized rats was determined.
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 4,5,6,7-tetrahydrobenzothiazole dopamine agonists display very low stereoselectivity in their interaction with dopamine receptors.
Year : 1991
Volume : 1
Issue : 4
First Page : 189
Last Page : 192
Authors : Jaen JC, Caprathe BW, Wise LD, Smith SJ, Pugsley TA, Heffner TG, Meltzer LT
|
Percentage inhibition of DA neural firing after administration the compound at a dose of 0.25 mg/kg through ip route in rats.
|
Rattus norvegicus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Dopamine autoreceptor agonists as potential antipsychotics. 3.6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine.
Year : 1991
Volume : 34
Issue : 9
First Page : 2736
Last Page : 2746
Authors : Caprathe BW, Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT, Parvez M.
Abstract : A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
|
Binding affinity to rat corpus striatum was determined using [3H]NPA as radioligand
|
Rattus norvegicus
|
10.5
nM
|
|
Journal : J. Med. Chem.
Title : 6,7-Dihydroxy-3-chromanamine: synthesis and pharmacological activity of an oxygen isostere of the dopamine agonist 6,7-dihydroxy-2-aminotetralin.
Year : 1984
Volume : 27
Issue : 10
First Page : 1340
Last Page : 1343
Authors : Horn AS, Kaptein B, Mulder TB, de Vries JB, Wynberg H.
Abstract : 6,7-Dihydroxy-3-chromanamine, the oxygen isostere of 6,7-dihydroxy-2-aminotetralin (6,7-ADTN), has been synthesized and its dopaminergic activity in various test systems determined. Following bilateral injection into the rat nucleus accumbens, a pattern of locomotor activity similar to that produced by 6,7-ADTN was observed. Its ability to displace N-n-propyl[3H]norapomorphine binding to homogenates of rat brain corpus striatum was found to be about 15 times weaker than 6,7-ADTN and apomorphine. Like 6,7-ADTN it failed to influence dopamine metabolism following an intraperitoneal injection. It is suggested that in addition to the 2-aminotetralins, the 3-chromanamines may be a potential source of new dopamine receptor agonists.
|
Tested in vitro for percent maximal inhibition in rat striatal slices (% of control) expressed as change of S1/S2 versus control at 1 uM
|
Rattus norvegicus
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships in the trans-hexahydroindolo[4,3-ab]phenanthridine ("benzergoline") series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective D1 agonist CY 208-243 and its implication for an "extended rotamer-based dopamine receptor model".
Year : 1993
Volume : 36
Issue : 8
First Page : 977
Last Page : 984
Authors : Seiler MP, Floersheim P, Markstein R, Widmer A.
Abstract : 4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described "rotamer-based dopamine receptor model", which allowed the localization of a "subtype selectivity-inducing site" (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed "additional" phenyl group of the benzergoline molecule.
|
Inhibitory concentration for half-maximal displacement of 1.0 nM [3H]ADTN specific binding from rat striatal membranes using 10E-5 sulpiride
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopaminergic properties of some exo- and endo-2-aminobenzonorbornenes designed as rigid analogue of dopamine.
Year : 1982
Volume : 25
Issue : 4
First Page : 363
Last Page : 368
Authors : Burn P, Crooks PA, Heatley F, Costall B, Naylor RJ, Nohria V.
Abstract : Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.
|
Inhibitory concentration half-maximal displacement of 1.0 nM [3H]NPA specific binding from rat striatal membranes using 10e-5 (+/-)ADTN
|
Rattus norvegicus
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopaminergic properties of some exo- and endo-2-aminobenzonorbornenes designed as rigid analogue of dopamine.
Year : 1982
Volume : 25
Issue : 4
First Page : 363
Last Page : 368
Authors : Burn P, Crooks PA, Heatley F, Costall B, Naylor RJ, Nohria V.
Abstract : Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.
|
Compound (2.0 mg/kg ip.) was evaluated for reversal of the increase in rat striatum DOPA accumulation produced by the pretreatment with GBL (750 mg/Kg, ip) and NSD 1015 (2 mg/Kg, ip)
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and dopaminergic activity of the enantiomers of 6-methyl-4,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine (PD 128483).
Year : 1991
Volume : 1
Issue : 10
First Page : 539
Last Page : 544
Authors : Jaen JC, Caprathe BW, Wise LD, Pugsley TA, Meltzer LT, Heffner TG
|
Compound was evaluated for inhibition of the spontaneous firing of substantia nigra DA neurons in anesthetized rats at 0.25 mg/Kg (ip)
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and dopaminergic activity of the enantiomers of 6-methyl-4,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine (PD 128483).
Year : 1991
Volume : 1
Issue : 10
First Page : 539
Last Page : 544
Authors : Jaen JC, Caprathe BW, Wise LD, Pugsley TA, Meltzer LT, Heffner TG
|
Agonist activity at human D4.4 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR
|
Homo sapiens
|
4.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at ferret D4 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR
|
Mustela putorius furo
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at rat D4 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR
|
Rattus norvegicus
|
5.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at human D2 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR
|
Homo sapiens
|
5.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at ferret D2 receptor in HEK293 cells coexpressing Galphaqo5 by FLIPR
|
Mustela putorius furo
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at rat D2 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR
|
Rattus norvegicus
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Displacement of [125I]7-OH-PIPAT from human D2L receptor expressed in HEK293 cell membrane
|
Homo sapiens
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Displacement of [3H]A369508 from human D4 receptor expressed in HEK293 cell membrane
|
Homo sapiens
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 25
First Page : 7450
Last Page : 7465
Authors : Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO.
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
|
Agonist activity at human recombinant dopamine D2 receptor expressed in rat pituitary cells assessed as inhibition of forskolin-stimulated cAMP accumulation
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.
Year : 2007
Volume : 17
Issue : 24
First Page : 6691
Last Page : 6696
Authors : Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S.
Abstract : This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
|
Agonist activity at human recombinant dopamine D3 receptor expressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP accumulation
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.
Year : 2007
Volume : 17
Issue : 24
First Page : 6691
Last Page : 6696
Authors : Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S.
Abstract : This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
|
Displacement of [3H]SCH-23390 from rat dopamine D1 receptor
|
Rattus norvegicus
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Advances in development of dopaminergic aporphinoids.
Year : 2007
Volume : 50
Issue : 2
First Page : 171
Last Page : 181
Authors : Zhang A, Zhang Y, Branfman AR, Baldessarini RJ, Neumeyer JL.
|
Displacement of [3H]raclopride from rat dopamine D2 receptor
|
Rattus norvegicus
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Advances in development of dopaminergic aporphinoids.
Year : 2007
Volume : 50
Issue : 2
First Page : 171
Last Page : 181
Authors : Zhang A, Zhang Y, Branfman AR, Baldessarini RJ, Neumeyer JL.
|
Displacement of [3H]neomonapride from dopamine D2 receptor in rat striatum
|
Rattus norvegicus
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and dopamine receptor affinities of N-alkyl-11-hydroxy-2-methoxynoraporphines: N-alkyl substituents determine D1 versus D2 receptor selectivity.
Year : 2008
Volume : 51
Issue : 4
First Page : 983
Last Page : 987
Authors : Si YG, Gardner MP, Tarazi FI, Baldessarini RJ, Neumeyer JL.
Abstract : We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxynoraporphines from thebaine and evaluated their binding affinities at dopamine D1 and D2 receptors in rat forebrain tissue. At D2 receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D2, Ki = 1.3 nM; D1, Ki = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D2, Ki = 44 nM; D1, Ki = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy-N-methyl-aporphine (D1 vs D2, Ki = 46 vs 235 nM) showed higher D1 than D2 affinity, indicating that N-alkyl substituents have major effects on D2 affinity and D2/D1 selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.
|
Agonist activity at human recombinant dopamine D1 receptor expressed in CHO cells assessed as stimulation of cAMP production
|
Homo sapiens
|
52.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.
Year : 2008
Volume : 16
Issue : 6
First Page : 3438
Last Page : 3444
Authors : Liu D, Dijkstra D, de Vries JB, Wikström HV.
Abstract : Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.
|
Agonist activity at human dopamine D2 receptor expressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.
Year : 2008
Volume : 16
Issue : 6
First Page : 3438
Last Page : 3444
Authors : Liu D, Dijkstra D, de Vries JB, Wikström HV.
Abstract : Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.
|
Displacement of [3H]SCH-23390 from human dopamine D1 receptor expressed in HEK293 cells
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological investigation of novel 2-aminothiazole-privileged aporphines.
Year : 2008
Volume : 16
Issue : 14
First Page : 6675
Last Page : 6681
Authors : Liu Z, Chen X, Yu L, Zhen X, Zhang A.
Abstract : A series of apomorphine ((-)-1, APO)-derived analogues ((+/-)-3, (-)-4-(-)-6) were designed and synthesized by hybridizing APO with a privileged 2-aminothiazole functionality which was lent from the orally available anti-parkinsonian drug, pramipexole (2). Among these hybridized compounds, catecholic aporphine (-)-6 shows good affinity at the D(2) receptor with K(i) of 328nM, slightly less potent (3-fold), but more selective against the D(1) receptor than that of the parent compound, APO. Although possessing reduced affinity at the D(2) receptor, aporphines 15 and 18 show significant potency at both the D(1) and 5-HT(1A) receptors. The former compound is equipotent at both receptors (K(i): 116 and 151nM, respectively), while the latter is 8-fold more potent at the D(1) (K(i): 78nM) than at the 5-HT(1A) receptors (K(i): 640nM). These results indicate that the catechol fragment is critical for the D(2) receptor binding of the anti-parkinsonian drug, APO ((-)-1), but not necessary for binding at the D(1) and 5-HT(1A) receptors.
|
Displacement of [3H]spiperone from human dopamine D2 receptor expressed in HEK293 cells
|
Homo sapiens
|
98.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological investigation of novel 2-aminothiazole-privileged aporphines.
Year : 2008
Volume : 16
Issue : 14
First Page : 6675
Last Page : 6681
Authors : Liu Z, Chen X, Yu L, Zhen X, Zhang A.
Abstract : A series of apomorphine ((-)-1, APO)-derived analogues ((+/-)-3, (-)-4-(-)-6) were designed and synthesized by hybridizing APO with a privileged 2-aminothiazole functionality which was lent from the orally available anti-parkinsonian drug, pramipexole (2). Among these hybridized compounds, catecholic aporphine (-)-6 shows good affinity at the D(2) receptor with K(i) of 328nM, slightly less potent (3-fold), but more selective against the D(1) receptor than that of the parent compound, APO. Although possessing reduced affinity at the D(2) receptor, aporphines 15 and 18 show significant potency at both the D(1) and 5-HT(1A) receptors. The former compound is equipotent at both receptors (K(i): 116 and 151nM, respectively), while the latter is 8-fold more potent at the D(1) (K(i): 78nM) than at the 5-HT(1A) receptors (K(i): 640nM). These results indicate that the catechol fragment is critical for the D(2) receptor binding of the anti-parkinsonian drug, APO ((-)-1), but not necessary for binding at the D(1) and 5-HT(1A) receptors.
|
Displacement of [3H]raclopride from dopamine D2 receptor in rat striatal membrane
|
Rattus norvegicus
|
11.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines.
Year : 2008
Volume : 16
Issue : 8
First Page : 4563
Last Page : 4568
Authors : Sipos A, Csutorás C, Berényi S, Uustare A, Rinken A.
Abstract : We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.
|
Displacement of [3H]raclopride from human cloned dopamine D2 receptor expressed in CHO cell membrane
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines.
Year : 2008
Volume : 16
Issue : 8
First Page : 4563
Last Page : 4568
Authors : Sipos A, Csutorás C, Berényi S, Uustare A, Rinken A.
Abstract : We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.
|
Displacement of [3H]raclopride from rat dopamine D2(short) receptor expressed in CHOK1 cells
|
Rattus norvegicus
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines.
Year : 2008
Volume : 16
Issue : 8
First Page : 4563
Last Page : 4568
Authors : Sipos A, Csutorás C, Berényi S, Uustare A, Rinken A.
Abstract : We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.
|
Displacement of [3H]SCH23390 from dopamine D1 receptor in mouse Ltk- fibroblast cells
|
Mus musculus
|
101.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines.
Year : 2008
Volume : 16
Issue : 8
First Page : 4563
Last Page : 4568
Authors : Sipos A, Csutorás C, Berényi S, Uustare A, Rinken A.
Abstract : We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of human aquaporin 4 M23 isoform expressed in Xenopus laevis oocytes at 20 uM
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of aquaporin 4 inhibitors using in vitro and in silico methods.
Year : 2009
Volume : 17
Issue : 1
First Page : 411
Last Page : 417
Authors : Huber VJ, Tsujita M, Nakada T.
Abstract : The in vitro inhibitory effects and in silico docking energies of 18 compounds with respect to aquaporin 4 (AQP4) were investigated. More than half of the compounds tested showed inhibitory activity in the in vitro functional assay and included the 5-HT(1B/1D) agonists sumatriptan, and rizatriptan. Moreover, the observed inhibitory activity of the compounds used in this study at 20 microM showed a strong correlation with their in silico docking energies, r(2)=0.64, which was consistent with that found in previous studies. The AQP4 inhibitory IC(50) values of three compounds, 2-(nicotinamido)-1,3,4-thiadiazole, sumatriptan and rizatriptan, were subsequently found to be 3, 11, and 2 microM, respectively.
|
Selectivity ratio of Ki for dopamine D1 receptor to Ki for dopamine D2 receptor in rat forebrain
|
Rattus norvegicus
|
532.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and neuropharmacological evaluation of esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines.
Year : 2009
Volume : 19
Issue : 1
First Page : 51
Last Page : 53
Authors : Si YG, Choi YK, Gardner MP, Tarazi FI, Baldessarini RJ, Neumeyer JL.
Abstract : We synthesized several esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines, assessed their affinities at dopamine D(1) and D(2) receptors in rat forebrain tissue and quantified their effects on motor activity in normal adult male rats. Tested compounds displayed moderate to high affinities to D(2) receptors but low affinities to D(1) receptors. The most D(2)-potent (K(i)=18.9nM) and selective novel agent (>529-fold vs D(1) sites) was R(-)-2-methoxy-11-acetyloxy-N-n-propylnoraporphine (compound 4b). At moderate doses, the compound proved to have prolonged behavioral locomotor activity.
|
Displacement of [3H]raclopride from rat dopamine D2short receptor expressed in CHO-K1 cells by liquid scintillation counting
|
Rattus norvegicus
|
11.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : N-Substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists.
Year : 2009
Volume : 17
Issue : 13
First Page : 4756
Last Page : 4762
Authors : Herm L, Berényi S, Vonk A, Rinken A, Sipos A.
Abstract : Two synthesis routes have been elaborated for the preparation of novel N-substituted-2-alkyl- and 2-arylnorapomorphines. The first one utilizes the traditional methodology of N-substitution of morphinans before acid-catalyzed rearrangements into aporphinoids, while our new approach involves the N-substitution directly on the aporphine backbone. The aimed compounds were obtained in similar overall yields in different synthesis routes and were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. These studies revealed remarkable affinity and selectivity of some compounds for D(2) over D(1) receptor subtypes. Partial or full agonist properties were confirmed for all tested compounds.
|
Agonist activity at rat dopamine D2short receptor expressed in CHO-K1 cells assessed as stimulation of [35S]GTPgammaS binding by liquid scintillation counting
|
Rattus norvegicus
|
53.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : N-Substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists.
Year : 2009
Volume : 17
Issue : 13
First Page : 4756
Last Page : 4762
Authors : Herm L, Berényi S, Vonk A, Rinken A, Sipos A.
Abstract : Two synthesis routes have been elaborated for the preparation of novel N-substituted-2-alkyl- and 2-arylnorapomorphines. The first one utilizes the traditional methodology of N-substitution of morphinans before acid-catalyzed rearrangements into aporphinoids, while our new approach involves the N-substitution directly on the aporphine backbone. The aimed compounds were obtained in similar overall yields in different synthesis routes and were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. These studies revealed remarkable affinity and selectivity of some compounds for D(2) over D(1) receptor subtypes. Partial or full agonist properties were confirmed for all tested compounds.
|
Displacement of [3H]SCH23390 from dopamine D1 receptor expressed in Ltk deficient fibroblast cells by liquid scintillation counting
|
None
|
72.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : N-Substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists.
Year : 2009
Volume : 17
Issue : 13
First Page : 4756
Last Page : 4762
Authors : Herm L, Berényi S, Vonk A, Rinken A, Sipos A.
Abstract : Two synthesis routes have been elaborated for the preparation of novel N-substituted-2-alkyl- and 2-arylnorapomorphines. The first one utilizes the traditional methodology of N-substitution of morphinans before acid-catalyzed rearrangements into aporphinoids, while our new approach involves the N-substitution directly on the aporphine backbone. The aimed compounds were obtained in similar overall yields in different synthesis routes and were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. These studies revealed remarkable affinity and selectivity of some compounds for D(2) over D(1) receptor subtypes. Partial or full agonist properties were confirmed for all tested compounds.
|
Displacement of [3H]spiperone from human dopamine D2 receptor at low affinity state expressed in HEK293 cells
|
Homo sapiens
|
244.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16).
Year : 2010
Volume : 53
Issue : 6
First Page : 2510
Last Page : 2520
Authors : Pettersson F, Pontén H, Waters N, Waters S, Sonesson C.
Abstract : Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.
|
Displacement of [3H]spiperone from human dopamine D2 receptor at high affinity state expressed in HEK293 cells
|
Homo sapiens
|
0.62
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16).
Year : 2010
Volume : 53
Issue : 6
First Page : 2510
Last Page : 2520
Authors : Pettersson F, Pontén H, Waters N, Waters S, Sonesson C.
Abstract : Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.
|
Antiproliferative activity against mouse neural precursor cells by MTT assay
|
Mus musculus
|
350.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Antiproliferative activity against mouse medulloblastoma cells harboring heterozygous ptch1 gene by MTT assay
|
Mus musculus
|
168.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Antiproliferative activity against mouse neural precursor cells by colony formation assay
|
Mus musculus
|
683.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Antiproliferative activity against human GBM2 cells by MTT assay
|
Homo sapiens
|
310.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Displacement of [3H]SCH23390 from dopamine D2 receptor low binding site in Sprague-Dawley rat striatum by scintillation counting
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors
Year : 2011
Volume : 2
Issue : 3
First Page : 189
Last Page : 194
Authors : Sromek AW, Si YG, Zhang T, George SR, Seeman P, Neumeyer JL.
Abstract : The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
|
Displacement of [3H]domperidone from dopamine D2 receptor high binding site in Sprague-Dawley rat striatum by scintillation counting
|
Rattus norvegicus
|
1.8
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors
Year : 2011
Volume : 2
Issue : 3
First Page : 189
Last Page : 194
Authors : Sromek AW, Si YG, Zhang T, George SR, Seeman P, Neumeyer JL.
Abstract : The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
|
Displacement of [3H]domperidone from human cloned dopamine D3 receptor expressed in mouse CCL1-3 cells by scintillation counting
|
Homo sapiens
|
2.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors
Year : 2011
Volume : 2
Issue : 3
First Page : 189
Last Page : 194
Authors : Sromek AW, Si YG, Zhang T, George SR, Seeman P, Neumeyer JL.
Abstract : The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
|
Binding affinity to dopamine D1 receptor low binding site by radioligand displacement assay
|
None
|
650.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors
Year : 2011
Volume : 2
Issue : 3
First Page : 189
Last Page : 194
Authors : Sromek AW, Si YG, Zhang T, George SR, Seeman P, Neumeyer JL.
Abstract : The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
|
Binding affinity to dopamine D1 receptor high binding site by radioligand displacement assay
|
None
|
4.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors
Year : 2011
Volume : 2
Issue : 3
First Page : 189
Last Page : 194
Authors : Sromek AW, Si YG, Zhang T, George SR, Seeman P, Neumeyer JL.
Abstract : The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.
|
Displacement of [3H]raclopride from rat D2 dopamine receptor expressed in CHOK1 cells after 90 mins by liquid scintillation counter scintillation counter
|
Rattus norvegicus
|
11.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New 2-thioether-substituted apomorphines as potent and selective dopamine D₂ receptor agonists.
Year : 2011
Volume : 46
Issue : 7
First Page : 2992
Last Page : 2999
Authors : Reinart R, Gyulai Z, Berényi S, Antus S, Vonk A, Rinken A, Sipos A.
Abstract : A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios.
|
Agonist activity at rat D2 dopamine receptor expressed in CHOK1 cells assessed as [35S]GTPgammaS binding after 90 mins by liquid scintillation counter
|
Rattus norvegicus
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New 2-thioether-substituted apomorphines as potent and selective dopamine D₂ receptor agonists.
Year : 2011
Volume : 46
Issue : 7
First Page : 2992
Last Page : 2999
Authors : Reinart R, Gyulai Z, Berényi S, Antus S, Vonk A, Rinken A, Sipos A.
Abstract : A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios.
|
Displacement of [3H]SCH23390 from human D1 dopamine receptor expressed in Ltk fibroblast cells after 60 mins by liquid scintillation counter
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New 2-thioether-substituted apomorphines as potent and selective dopamine D₂ receptor agonists.
Year : 2011
Volume : 46
Issue : 7
First Page : 2992
Last Page : 2999
Authors : Reinart R, Gyulai Z, Berényi S, Antus S, Vonk A, Rinken A, Sipos A.
Abstract : A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios.
|
Displacement of [3H]SCH23390 from human D1 receptor expressed in HEK293 cells
|
Homo sapiens
|
660.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Chemoenzymatic synthesis and evaluation of 3-azabicyclo[3.2.0]heptane derivatives as dopaminergic ligands.
Year : 2012
Volume : 55
First Page : 255
Last Page : 261
Authors : Reinart-Okugbeni R, Ausmees K, Kriis K, Werner F, Rinken A, Kanger T.
Abstract : New 3-azabicyclo[3.2.0]heptane derivatives were synthesized using a multicomponent reaction. Racemic compounds were efficiently resolved by kinetic resolution with immobilized lipase B of Candida antarctica (Novozym 435). The obtained compounds demonstrated greater binding affinity at D(2L) and D(3) dopamine receptors compared to D(1) binding sites, and individual enantiomers of the same compound possessed distinct affinities.
|
Displacement of [3H]raclopride from human D2L receptor expressed in HEK293 cells
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Chemoenzymatic synthesis and evaluation of 3-azabicyclo[3.2.0]heptane derivatives as dopaminergic ligands.
Year : 2012
Volume : 55
First Page : 255
Last Page : 261
Authors : Reinart-Okugbeni R, Ausmees K, Kriis K, Werner F, Rinken A, Kanger T.
Abstract : New 3-azabicyclo[3.2.0]heptane derivatives were synthesized using a multicomponent reaction. Racemic compounds were efficiently resolved by kinetic resolution with immobilized lipase B of Candida antarctica (Novozym 435). The obtained compounds demonstrated greater binding affinity at D(2L) and D(3) dopamine receptors compared to D(1) binding sites, and individual enantiomers of the same compound possessed distinct affinities.
|
Displacement of [3H]raclopride from human D3 receptor expressed in HEK293 cells
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Chemoenzymatic synthesis and evaluation of 3-azabicyclo[3.2.0]heptane derivatives as dopaminergic ligands.
Year : 2012
Volume : 55
First Page : 255
Last Page : 261
Authors : Reinart-Okugbeni R, Ausmees K, Kriis K, Werner F, Rinken A, Kanger T.
Abstract : New 3-azabicyclo[3.2.0]heptane derivatives were synthesized using a multicomponent reaction. Racemic compounds were efficiently resolved by kinetic resolution with immobilized lipase B of Candida antarctica (Novozym 435). The obtained compounds demonstrated greater binding affinity at D(2L) and D(3) dopamine receptors compared to D(1) binding sites, and individual enantiomers of the same compound possessed distinct affinities.
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) wild type dopamine D3 receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
29.4
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D3 trunk/D3 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
27.2
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D3 trunk/D2 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
24.3
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D2 trunk/D3 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
69.5
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) wild type dopamine D2 receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
118.0
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D2 trunk/D2 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
135.0
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Agonist activity at human dopamine D2L receptor expressed in HEK293 cells assessed as forskolin-stimulated cAMP accumulation after 15 mins
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-substituted apomorphines as potent dopamine agonists.
Year : 2013
Volume : 21
Issue : 14
First Page : 4143
Last Page : 4150
Authors : Reinart-Okugbeni R, Vonk A, Uustare A, Gyulai Z, Sipos A, Rinken A.
Abstract : A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
|
Agonist activity at human dopamine D1 receptor expressed in HEK293 cells assessed as cAMP accumulation after 15 mins
|
Homo sapiens
|
25.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-substituted apomorphines as potent dopamine agonists.
Year : 2013
Volume : 21
Issue : 14
First Page : 4143
Last Page : 4150
Authors : Reinart-Okugbeni R, Vonk A, Uustare A, Gyulai Z, Sipos A, Rinken A.
Abstract : A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
|
Displacement of [3H]raclopride from human dopamine D3 receptor expressed in HEK293 cells by scintillation counting analysis
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-substituted apomorphines as potent dopamine agonists.
Year : 2013
Volume : 21
Issue : 14
First Page : 4143
Last Page : 4150
Authors : Reinart-Okugbeni R, Vonk A, Uustare A, Gyulai Z, Sipos A, Rinken A.
Abstract : A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
|
Displacement of [3H]raclopride from human dopamine D2L receptor expressed in HEK293 cells by scintillation counting analysis
|
Homo sapiens
|
53.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-substituted apomorphines as potent dopamine agonists.
Year : 2013
Volume : 21
Issue : 14
First Page : 4143
Last Page : 4150
Authors : Reinart-Okugbeni R, Vonk A, Uustare A, Gyulai Z, Sipos A, Rinken A.
Abstract : A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
|
Displacement of [3H]SCH23390 from human dopamine D1 receptor expressed in HEK293 cells by scintillation counting analysis
|
Homo sapiens
|
492.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-substituted apomorphines as potent dopamine agonists.
Year : 2013
Volume : 21
Issue : 14
First Page : 4143
Last Page : 4150
Authors : Reinart-Okugbeni R, Vonk A, Uustare A, Gyulai Z, Sipos A, Rinken A.
Abstract : A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
|
Displacement of [3H]spiperone from human recombinant dopamine D2L receptor expressed in CHOFlpIn cells after 3 hrs by liquid scintillation counting
|
Homo sapiens
|
117.0
nM
|
|
Journal : MedChemComm
Title : Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor
Year : 2013
Volume : 4
Issue : 9
First Page : 1290
Last Page : 1296
Authors : Shonberg J, Lane JR, Scammells PJ, Capuano B
|
Agonist activity at human recombinant dopamine D2L receptor expressed in CHOFlpIn cells assessed as ERK1/2 phosphorylation by alphascreen assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : MedChemComm
Title : Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor
Year : 2013
Volume : 4
Issue : 9
First Page : 1290
Last Page : 1296
Authors : Shonberg J, Lane JR, Scammells PJ, Capuano B
|
Inhibition of prolactin release in reserpinized rat assessed as reduction in serum prolactin level at 1 mg, ip after 1 hr post dose by radioimmunoassay relative to untreated control
|
Rattus norvegicus
|
29.0
%
|
|
Journal : J. Med. Chem.
Title : Ergoline congeners as potential inhibitors of prolactin release. 3. Derivatives of 3-phenylpiperidine.
Year : 1977
Volume : 20
Issue : 1
First Page : 85
Last Page : 88
Authors : Rusterholz DB, Barfknecht CF, Clemens JA.
Abstract : In a continuation of our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared several derivatives of 3-phenylpiperidine. These congeners have been evaluated for inhibition of prolactin release in vivo and are for the most part inactive.
|
Inhibition of prolactin secretion in rat assessed as serum prolactin level at 1 ug, ip after 1 hr by radioimmunoassay relative to control
|
Rattus norvegicus
|
29.0
%
|
|
Journal : J. Med. Chem.
Title : Ergoline congeners as potential inhibitors of prolactin release. 2.
Year : 1976
Volume : 19
Issue : 1
First Page : 99
Last Page : 102
Authors : Rusterholz DB, Barfknecht CF, Clemens JA.
Abstract : In our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared one indolealkylamine and several 2-aminotetralin derivatives. These congeners have been evaluated for inhibition of prolactin release in vivo. One congener, 5,8-dihydroxy-2-dimethylaminotetralin, and the drug M-7 significantly inhibited prolactin secretion.
|
Agonist activity at human dopamine D2 receptor expressed in CHOK1 cells assessed as calcium mobilization by radiometric and luminescence plate counting method
|
Homo sapiens
|
4.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.
Year : 2015
Volume : 92
First Page : 221
Last Page : 235
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Śniecikowska J, Pawłowski M, Kazek G, Siwek A, Jastrzębska-Więsek M, Partyka A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
|
Agonist activity at dopamine D2 receptor short isoform (unknown origin) expressed in mouse NIH/3T3 cells by R-SAT assay
|
Homo sapiens
|
575.44
nM
|
|
Title : Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
Year : 2004
|
Inhibition of biotin-labelled L-p53 binding to L-MDM2 (25 to 109 residues) (unknown origin) by FAM labeled P4 peptide based fluorescence polarization assay
|
Homo sapiens
|
215.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Investigation of the inhibitory mechanism of apomorphine against MDM2-p53 interaction.
Year : 2017
Volume : 27
Issue : 11
First Page : 2571
Last Page : 2574
Authors : Ishiba H, Noguchi T, Shu K, Ohno H, Honda K, Kondoh Y, Osada H, Fujii N, Oishi S.
Abstract : Mirror-image screening using d-proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2-p53 interaction inhibitors, we identified that NPD6878 (R-(-)-apomorphine) inhibited both the native l-MDM2-l-p53 interaction and the mirror-image d-MDM2-d-p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2-p53 interaction. In this study, we investigated the inhibitory mechanism of both enantiomers of apomorphine against the MDM2-p53 interaction. Achiral oxoapomorphine, which was converted from chiral apomorphines under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2, leading to the inhibitory effect against the binding to p53.
|
Inhibition of biotin-labelled D-p53 binding to D-MDM2 (25 to 109 residues) (unknown origin) by FAM labeled P4 peptide based fluorescence polarization assay
|
Homo sapiens
|
195.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Investigation of the inhibitory mechanism of apomorphine against MDM2-p53 interaction.
Year : 2017
Volume : 27
Issue : 11
First Page : 2571
Last Page : 2574
Authors : Ishiba H, Noguchi T, Shu K, Ohno H, Honda K, Kondoh Y, Osada H, Fujii N, Oishi S.
Abstract : Mirror-image screening using d-proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2-p53 interaction inhibitors, we identified that NPD6878 (R-(-)-apomorphine) inhibited both the native l-MDM2-l-p53 interaction and the mirror-image d-MDM2-d-p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2-p53 interaction. In this study, we investigated the inhibitory mechanism of both enantiomers of apomorphine against the MDM2-p53 interaction. Achiral oxoapomorphine, which was converted from chiral apomorphines under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2, leading to the inhibitory effect against the binding to p53.
|
Agonist activity at human D2 receptor expressed in CHO-K1 cells co-expressing Galphaqi5 assessed as increase in calcium mobilization measured for 30 secs by aequorin-derived luminescence assay
|
Homo sapiens
|
12.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.
Year : 2018
Volume : 28
Issue : 11
First Page : 2039
Last Page : 2049
Authors : Pańczyk K, Pytka K, Jakubczyk M, Rapacz A, Sałat K, Furgała A, Siwek A, Głuch-Lutwin M, Gryboś A, Słoczyńska K, Pękala E, Żmudzki P, Bucki A, Kołaczkowski M, Żelaszczyk D, Marona H, Waszkielewicz AM.
Abstract : Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as - at higher doses - for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).
|
Inhibition of amyloid beta (1 to 42) (unknown origin) aggregation at 5 uM after 48 hrs by Thioflavin-T fluorescence assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg Med Chem
Title : Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine.
Year : 2018
Volume : 26
Issue : 8
First Page : 1538
Last Page : 1546
Authors : Hanaki M, Murakami K, Katayama S, Akagi KI, Irie K.
Abstract : (R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity. 1H-15N SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13,14, Gln15, and Lys16 of the Aβ42 monomer. These regions form intermolecular β-sheets in Aβ42 aggregates. Since 3 did not perturb the chemical shift of monomeric Aβ42, we performed aggregation experiments using 1,1,1,3,3,3-hexafluoro-2-propanol-treated Aβ42 to investigate whether 3 associates with Aβ42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate Aβ42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the β-sheet of Aβ42 nuclei, thereby suppressing further aggregation.
|
Agonist activity at C-terminal RLuc8-fused D1R (unknown origin) transfected in human HEK293T cells co-expressing N-terminal Venus-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment measured after 5 mins in presence of coelenterazine H by BRET assay
|
Homo sapiens
|
501.19
nM
|
|
Agonist activity at C-terminal RLuc8-fused D1R (unknown origin) transfected in human HEK293T cells co-expressing N-terminal Venus-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment measured after 5 mins in presence of coelenterazine H by BRET assay
|
Homo sapiens
|
520.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands.
Year : 2020
Volume : 11
Issue : 3
First Page : 385
Last Page : 392
Authors : Park H, Urs AN, Zimmerman J, Liu C, Wang Q, Urs NM.
Abstract : Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
|
Agonist activity at C-terminal RLuc8-fused D2 long receptor (unknown origin) transfected in human HEK293T cells co-expressing N-terminal Venus-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment measured after 5 mins in presence of coelenterazine H by BRET assay
|
Homo sapiens
|
10.0
nM
|
|
Agonist activity at C-terminal RLuc8-fused D2 long receptor (unknown origin) transfected in human HEK293T cells co-expressing N-terminal Venus-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment measured after 5 mins in presence of coelenterazine H by BRET assay
|
Homo sapiens
|
10.1
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands.
Year : 2020
Volume : 11
Issue : 3
First Page : 385
Last Page : 392
Authors : Park H, Urs AN, Zimmerman J, Liu C, Wang Q, Urs NM.
Abstract : Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
|
Agonist activity at D1R (unknown origin) transfected in human HEK293T cells assessed as increase in cAMP accumulation incubated for 2 hrs by cAMP Glo-sensor assay
|
Homo sapiens
|
3.981
nM
|
|
Agonist activity at D1R (unknown origin) transfected in human HEK293T cells assessed as increase in cAMP accumulation incubated for 2 hrs by cAMP Glo-sensor assay
|
Homo sapiens
|
3.77
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands.
Year : 2020
Volume : 11
Issue : 3
First Page : 385
Last Page : 392
Authors : Park H, Urs AN, Zimmerman J, Liu C, Wang Q, Urs NM.
Abstract : Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
|
Agonist activity at D2 long receptor (unknown origin) transfected in human HEK293T cells assessed as increase in cAMP accumulation incubated for 2 hrs by cAMP Glo-sensor assay
|
Homo sapiens
|
1.585
nM
|
|
Agonist activity at D2 long receptor (unknown origin) transfected in human HEK293T cells assessed as increase in cAMP accumulation incubated for 2 hrs by cAMP Glo-sensor assay
|
Homo sapiens
|
1.61
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands.
Year : 2020
Volume : 11
Issue : 3
First Page : 385
Last Page : 392
Authors : Park H, Urs AN, Zimmerman J, Liu C, Wang Q, Urs NM.
Abstract : Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure-functional-selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
|
Displacement of [3H]-raclopride from human D2 receptor expressed in HEK cells incubated for 1 hr by Cheng-Prusoff analysis based microbeta scintillation counting method
|
Homo sapiens
|
42.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT<sub>1A</sub> receptor ligands.
Year : 2019
Volume : 180
First Page : 383
Last Page : 397
Authors : Ślifirski G, Król M, Kleps J, Podsadni P, Belka M, Bączek T, Siwek A, Stachowicz K, Szewczyk B, Nowak G, Bojarski A, Kozioł AE, Turło J, Herold F.
Abstract : Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT<sub>1A</sub> receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT<sub>1A</sub> K<sub>i</sub> = 8-87 nM; SERT K<sub>i</sub> = 8-52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D<sub>2</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub>) showed their selectivity towards 5-HT<sub>1A</sub> receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT<sub>1A</sub> receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT<sub>1A</sub>-R and SERT) compared to the precursors.
|
Displacement of [3H]-raclopride from recombinant human D2 receptor expressed in HEK293 cells measured after 1 hr by microbeta scintillation counting analysis
|
Homo sapiens
|
42.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands.
Year : 2019
Volume : 166
First Page : 144
Last Page : 158
Authors : Ślifirski G, Król M, Kleps J, Ulenberg S, Belka M, Bączek T, Siwek A, Stachowicz K, Szewczyk B, Nowak G, Bojarski A, Kozioł AE, Turło J, Herold F.
Abstract : The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1-9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.
|
Displacement of [3H]8-OH-DPAT from human 5-HT1A receptor expressed in CHO cells incubated for 150 mins by radio ligand binding assay
|
Homo sapiens
|
117.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.
Year : 2020
Volume : 30
Issue : 8
First Page : 127053
Last Page : 127053
Authors : Karki A, Juarez R, Namballa HK, Alberts I, Harding WW.
Abstract : New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors and at human dopamine D<sub>1</sub>, D<sub>2</sub> and D<sub>5</sub> receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D<sub>5</sub> receptor, thus attaining D<sub>1</sub> versus D<sub>5</sub> selectivity. Compound 20c was the most potent D<sub>1</sub> ligand identified. Docking studies at D<sub>1</sub> and D<sub>5</sub> receptors indicate that the binding mode of 20c at the D<sub>1</sub> receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D<sub>5</sub> receptor, accounting for its D<sub>1</sub> versus D<sub>5</sub> selectivity. Considering the lack of affinity for the D<sub>5</sub> receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D<sub>1</sub> receptor tools.
|
Displacement of [3H]ketanserin from human 5HT2A receptor expressed in CHO cells incubated for 40 mins by radio ligand binding assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.
Year : 2020
Volume : 30
Issue : 8
First Page : 127053
Last Page : 127053
Authors : Karki A, Juarez R, Namballa HK, Alberts I, Harding WW.
Abstract : New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors and at human dopamine D<sub>1</sub>, D<sub>2</sub> and D<sub>5</sub> receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D<sub>5</sub> receptor, thus attaining D<sub>1</sub> versus D<sub>5</sub> selectivity. Compound 20c was the most potent D<sub>1</sub> ligand identified. Docking studies at D<sub>1</sub> and D<sub>5</sub> receptors indicate that the binding mode of 20c at the D<sub>1</sub> receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D<sub>5</sub> receptor, accounting for its D<sub>1</sub> versus D<sub>5</sub> selectivity. Considering the lack of affinity for the D<sub>5</sub> receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D<sub>1</sub> receptor tools.
|
Displacement of [3H]SCH23390 from human D1 receptor expressed in L cells incubated for 60 mins by radio ligand binding assay
|
Homo sapiens
|
372.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.
Year : 2020
Volume : 30
Issue : 8
First Page : 127053
Last Page : 127053
Authors : Karki A, Juarez R, Namballa HK, Alberts I, Harding WW.
Abstract : New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors and at human dopamine D<sub>1</sub>, D<sub>2</sub> and D<sub>5</sub> receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D<sub>5</sub> receptor, thus attaining D<sub>1</sub> versus D<sub>5</sub> selectivity. Compound 20c was the most potent D<sub>1</sub> ligand identified. Docking studies at D<sub>1</sub> and D<sub>5</sub> receptors indicate that the binding mode of 20c at the D<sub>1</sub> receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D<sub>5</sub> receptor, accounting for its D<sub>1</sub> versus D<sub>5</sub> selectivity. Considering the lack of affinity for the D<sub>5</sub> receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D<sub>1</sub> receptor tools.
|
Displacement of [125I]iodosulpride from human D2 receptor expressed in CHO cells incubated for 40 mins by radio ligand binding assay
|
Homo sapiens
|
82.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.
Year : 2020
Volume : 30
Issue : 8
First Page : 127053
Last Page : 127053
Authors : Karki A, Juarez R, Namballa HK, Alberts I, Harding WW.
Abstract : New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors and at human dopamine D<sub>1</sub>, D<sub>2</sub> and D<sub>5</sub> receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D<sub>5</sub> receptor, thus attaining D<sub>1</sub> versus D<sub>5</sub> selectivity. Compound 20c was the most potent D<sub>1</sub> ligand identified. Docking studies at D<sub>1</sub> and D<sub>5</sub> receptors indicate that the binding mode of 20c at the D<sub>1</sub> receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D<sub>5</sub> receptor, accounting for its D<sub>1</sub> versus D<sub>5</sub> selectivity. Considering the lack of affinity for the D<sub>5</sub> receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D<sub>1</sub> receptor tools.
|
Displacement of [3H]SCH23390 from human D5 receptor expressed in CH4Cl cells incubated for 60 mins by radio ligand binding assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.
Year : 2020
Volume : 30
Issue : 8
First Page : 127053
Last Page : 127053
Authors : Karki A, Juarez R, Namballa HK, Alberts I, Harding WW.
Abstract : New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors and at human dopamine D<sub>1</sub>, D<sub>2</sub> and D<sub>5</sub> receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D<sub>5</sub> receptor, thus attaining D<sub>1</sub> versus D<sub>5</sub> selectivity. Compound 20c was the most potent D<sub>1</sub> ligand identified. Docking studies at D<sub>1</sub> and D<sub>5</sub> receptors indicate that the binding mode of 20c at the D<sub>1</sub> receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D<sub>5</sub> receptor, accounting for its D<sub>1</sub> versus D<sub>5</sub> selectivity. Considering the lack of affinity for the D<sub>5</sub> receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D<sub>1</sub> receptor tools.
