|
Displacement of [3H]clonidine from Alpha-2 adrenergic receptor of rat brain membranes
|
Rattus norvegicus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs.
Year : 1982
Volume : 25
Issue : 12
First Page : 1389
Last Page : 1401
Authors : Timmermans PB, van Zwieten PA.
|
Inhibition of [3H]prazosin binding to human Alpha-1D adrenergic receptor expressed in CHO cells
|
Homo sapiens
|
289.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Binding affinity against Alpha-1D adrenergic receptor, from human clones.
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Antagonistic activity against Alpha-2 adrenergic receptor in the prostatic portion of the rat vas deferens
|
None
|
19.5
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for 2-substituted imidazoles as alpha 2-adrenoceptor antagonists.
Year : 1982
Volume : 25
Issue : 6
First Page : 666
Last Page : 670
Authors : Caroon JM, Clark RD, Kluge AF, Olah R, Repke DB, Unger SH, Michel AD, Whiting RL.
Abstract : Several 2-[(1,4-benzodioxan-2-yl)alkyl]imidazoles were prepared and evaluated for their blocking activity and relative selectivity on presynaptic (alpha 2) and postsynaptic (alpha 1) receptors in the isolated rat vas deferens. 1-Ethyl-2-[(1,4-benzodioxan 2-yl)methyl]imidazole (13) was the most selective alpha 2-adrenoceptor antagonist of the series and was, for practical purposes, devoid of alpha 1-adrenoceptor antagonist activity. The lipophilicity of 13 (log D = 2.31) indicated that it would have an excellent chance to enter the central nervous system. Compound 13 was selected for clinical evaluation as an antidepressant agent.
|
Antagonistic activity against alpha-2 adrenergic receptor in rat vas deferens
|
None
|
26.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines as alpha 2-adrenoceptor antagonists.
Year : 1988
Volume : 31
Issue : 7
First Page : 1421
Last Page : 1426
Authors : Ward TJ, White JF, Lattimer N, Rhodes KF, Sharma S, Waterfall JF.
Abstract : A series of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines were synthesized and examined for alpha 2- and alpha 1-adrenoceptor antagonist activity on the rat vas deferens and anococcygeus muscle, respectively. A number of compounds in this series were shown to be potent and selective alpha 2-adrenoceptor antagonists. Studies on the resolved enantiomers of compounds 6, 10, and 16 showed that alpha 2-adrenoceptor antagonist activity resided primarily in the 2R,11bS isomers, related to the absolute configuration of the alpha 2-antagonist yohimbine, such that the benzene ring and sulfonamide groups in this series were superimposable on the pyrrole and ester groups of yohimbine.
|
Antagonistic activity against presynaptic alpha-2 adrenergic receptor in isolated rat vas deferens using xylazine as agonist
|
None
|
19.05
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic activity against clonidine-stimulated rat vas deferens presynaptic alpha-2 adrenergic receptor
|
Rattus norvegicus
|
22.39
nM
|
|
Journal : J. Med. Chem.
Title : Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.
Year : 1984
Volume : 27
Issue : 9
First Page : 1182
Last Page : 1185
Authors : Saari WS, Halczenko W, Huff JR, Guare JP, Hunt CA, Randall WC, Lotti VJ, Yarbrough GG.
Abstract : A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.
|
Antagonistic potency of compound for Alpha-2 adrenergic receptor
|
None
|
19.95
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
In vitro binding affinity was measured as the inhibition of [3H]WB-4101 binding to alpha-1 adrenergic receptor of rat cortical membranes
|
None
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Year : 1986
Volume : 29
Issue : 8
First Page : 1394
Last Page : 1398
Authors : Guérémy C, Audiau F, Renault C, Benavides J, Uzan A, Le Fur G.
Abstract : A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
|
Presynaptic antagonistic activity against alpha-2 adrenergic receptor from rat, isolated, field-stimulated vas deferens, using clonidine as the agonist
|
None
|
22.39
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1983
Volume : 26
Issue : 12
First Page : 1696
Last Page : 1701
Authors : Saari WS, Halczenko W, King SW, Huff JR, Guare JP, Hunt CA, Randall WC, Anderson PS, Lotti VJ, Taylor DA.
Abstract : A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.
|
Alpha-2 adrenergic receptor antagonistic activity in rat vas deferens vs clonidine
|
None
|
12.3
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
The compound was evaluated for the alpha-2 adrenergic receptor antagonistic activity in rat vas deferens vs methoxamine alpha1 adrenoceptor antagonism
|
None
|
123.03
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
Binding affinity against Alpha-2 adrenergic receptor in rat cerebral cortical membrane, determined using [3H]- yohimbine as the radioligand
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : (8a alpha,12a alpha,13a alpha)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridi ne, a potent and highly selective alpha 2-adrenoceptor antagonist.
Year : 1989
Volume : 32
Issue : 9
First Page : 2034
Last Page : 2036
Authors : Clark RD, Repke DB, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
|
Binding affinity against Alpha-1D adrenergic receptor, from rat clones.
|
Rattus norvegicus
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity to alpha-2 adrenergic receptor determined by measurement of [3H]yohimbine displacement from rat cortical membrane
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationships of 12-sulfonyl derivatives of 5,8,8a,9,10,11,12,12a,13,13a-decahydro-6H-isoquino[2,1-g][1 ,6] naphthyridines at alpha-adrenoceptors.
Year : 1991
Volume : 34
Issue : 2
First Page : 705
Last Page : 717
Authors : Clark RD, Repke DB, Berger J, Nelson JT, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
Abstract : Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.
|
Binding affinity to the alpha-2 adrenergic receptor of rat cerebral cortex assayed using [3H]idazoxan as radioligand
|
None
|
56.23
nM
|
|
Journal : J. Med. Chem.
Title : Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for alpha-adrenoceptors. Differential affinity of imidazolines for the [3H]idazoxan-labeled alpha 2-adrenoceptor vs the [3H]yohimbine-labeled site.
Year : 1990
Volume : 33
Issue : 2
First Page : 596
Last Page : 600
Authors : Clark RD, Berger J, Garg P, Weinhardt KK, Spedding M, Kilpatrick AT, Brown CM, MacKinnon AC.
Abstract : A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquinolin-2- ylmethyl)imidazoline, were found to be selective alpha 2-adrenoceptor ligands on the basis of displacement of [3H]yohimbine from rat cerebral cortical membranes. One compound, 2-[(8-chloro tetrahydroisoquinolin-2-yl)methyl]imidazoline (5m), showed a 36-fold difference in affinity for the [3H]idazoxan-labeled alpha 2-adrenoceptor relative to the [3H]yohimbine-labeled site, which may be evidence for alpha 2-adrenoceptor subtypes.
|
Binding affinity to alpha-2 adrenergic receptor of rat cerebral cortex assayed using [3H]yohimbine as radioligand
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for alpha-adrenoceptors. Differential affinity of imidazolines for the [3H]idazoxan-labeled alpha 2-adrenoceptor vs the [3H]yohimbine-labeled site.
Year : 1990
Volume : 33
Issue : 2
First Page : 596
Last Page : 600
Authors : Clark RD, Berger J, Garg P, Weinhardt KK, Spedding M, Kilpatrick AT, Brown CM, MacKinnon AC.
Abstract : A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquinolin-2- ylmethyl)imidazoline, were found to be selective alpha 2-adrenoceptor ligands on the basis of displacement of [3H]yohimbine from rat cerebral cortical membranes. One compound, 2-[(8-chloro tetrahydroisoquinolin-2-yl)methyl]imidazoline (5m), showed a 36-fold difference in affinity for the [3H]idazoxan-labeled alpha 2-adrenoceptor relative to the [3H]yohimbine-labeled site, which may be evidence for alpha 2-adrenoceptor subtypes.
|
Compound was evaluated for the displacement of [3H]yohimbine in acetonitrile/acetic acid anti-corynanthine MIPs for Alpha-2 adrenergic receptor
|
None
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Recognition in molecularly imprinted polymer 2-adrenoreceptor mimics
Year : 1996
Volume : 6
Issue : 18
First Page : 2237
Last Page : 2242
Authors : Berglund J, Nicholls IA, Lindbladh C, Mosbach K
|
Dissociation constant in high affinity sites where the binding is in 50 mM phosphate buffer for Alpha-2 adrenergic receptor
|
None
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Recognition in molecularly imprinted polymer 2-adrenoreceptor mimics
Year : 1996
Volume : 6
Issue : 18
First Page : 2237
Last Page : 2242
Authors : Berglund J, Nicholls IA, Lindbladh C, Mosbach K
|
Dissociation constant in high affinity sites where the binding is in acetonitrile/acetic acid for Alpha-2 adrenergic receptor
|
None
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Recognition in molecularly imprinted polymer 2-adrenoreceptor mimics
Year : 1996
Volume : 6
Issue : 18
First Page : 2237
Last Page : 2242
Authors : Berglund J, Nicholls IA, Lindbladh C, Mosbach K
|
Alpha-1 adrenergic receptor pA2 value against norepinephrine in vitro experiment in rat anococcygeus.
|
None
|
323.59
nM
|
|
Journal : J. Med. Chem.
Title : alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.
Year : 1983
Volume : 26
Issue : 6
First Page : 823
Last Page : 831
Authors : Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF.
Abstract : The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.
|
Antagonistic activity against Alpha-1 adrenergic receptor in the epidermal portion of the rat vas deferens
|
None
|
616.6
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for 2-substituted imidazoles as alpha 2-adrenoceptor antagonists.
Year : 1982
Volume : 25
Issue : 6
First Page : 666
Last Page : 670
Authors : Caroon JM, Clark RD, Kluge AF, Olah R, Repke DB, Unger SH, Michel AD, Whiting RL.
Abstract : Several 2-[(1,4-benzodioxan-2-yl)alkyl]imidazoles were prepared and evaluated for their blocking activity and relative selectivity on presynaptic (alpha 2) and postsynaptic (alpha 1) receptors in the isolated rat vas deferens. 1-Ethyl-2-[(1,4-benzodioxan 2-yl)methyl]imidazole (13) was the most selective alpha 2-adrenoceptor antagonist of the series and was, for practical purposes, devoid of alpha 1-adrenoceptor antagonist activity. The lipophilicity of 13 (log D = 2.31) indicated that it would have an excellent chance to enter the central nervous system. Compound 13 was selected for clinical evaluation as an antidepressant agent.
|
Antagonistic activity against alpha-1 adrenergic receptor in isolated rat anococcygeus muscle
|
None
|
263.03
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines as alpha 2-adrenoceptor antagonists.
Year : 1988
Volume : 31
Issue : 7
First Page : 1421
Last Page : 1426
Authors : Ward TJ, White JF, Lattimer N, Rhodes KF, Sharma S, Waterfall JF.
Abstract : A series of 2-sulfonamido-1,3,4,6,7,11b alpha-hexahydro-2H-benzo[a]quinolizines were synthesized and examined for alpha 2- and alpha 1-adrenoceptor antagonist activity on the rat vas deferens and anococcygeus muscle, respectively. A number of compounds in this series were shown to be potent and selective alpha 2-adrenoceptor antagonists. Studies on the resolved enantiomers of compounds 6, 10, and 16 showed that alpha 2-adrenoceptor antagonist activity resided primarily in the 2R,11bS isomers, related to the absolute configuration of the alpha 2-antagonist yohimbine, such that the benzene ring and sulfonamide groups in this series were superimposable on the pyrrole and ester groups of yohimbine.
|
Antagonistic activity against postsynaptic Alpha-1 adrenergic receptor in isolated rat vas deferens using (-)-phenylephrine as agonist
|
None
|
89.13
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic activity upon postsynaptic alpha-1 adrenergic receptor was determined in the rat isolated, field stimulated vas deferens using methoxamine
|
None
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.
Year : 1984
Volume : 27
Issue : 9
First Page : 1182
Last Page : 1185
Authors : Saari WS, Halczenko W, Huff JR, Guare JP, Hunt CA, Randall WC, Lotti VJ, Yarbrough GG.
Abstract : A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.
|
Antagonistic potency of compound for Alpha-1 adrenergic receptor
|
None
|
630.96
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Presynaptic antagonistic activity against alpha-1 adrenergic receptor from rat, isolated, field-stimulated vas deferens, using methoxamine as the agonist
|
None
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1983
Volume : 26
Issue : 12
First Page : 1696
Last Page : 1701
Authors : Saari WS, Halczenko W, King SW, Huff JR, Guare JP, Hunt CA, Randall WC, Anderson PS, Lotti VJ, Taylor DA.
Abstract : A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.
|
Binding activity against alpha-2 adrenergic receptor from calf cerebral cortex, using [3H]clonidine as the radioligand
|
None
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1983
Volume : 26
Issue : 12
First Page : 1696
Last Page : 1701
Authors : Saari WS, Halczenko W, King SW, Huff JR, Guare JP, Hunt CA, Randall WC, Anderson PS, Lotti VJ, Taylor DA.
Abstract : A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.
|
Displacement of [3H]clonidine from calf cerebral cortex alpha-2 adrenergic receptor
|
Bos taurus
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.
Year : 1984
Volume : 27
Issue : 9
First Page : 1182
Last Page : 1185
Authors : Saari WS, Halczenko W, Huff JR, Guare JP, Hunt CA, Randall WC, Lotti VJ, Yarbrough GG.
Abstract : A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.
|
Evaluated for its ability to displace [3H]clonidine from alpha-2 adrenergic receptor of calf cerebral cortex
|
None
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin -2-yl)-N- methyl-2-hydroxyethane-sulfonamide: a potent and selective alpha 2-adrenoceptor antagonist.
Year : 1985
Volume : 28
Issue : 12
First Page : 1756
Last Page : 1759
Authors : Huff JR, Anderson PS, Baldwin JJ, Clineschmidt BV, Guare JP, Lotti VJ, Pettibone DJ, Randall WC, Vacca JP.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in bovine pineal
|
None
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity against human Alpha-2A adrenergic receptor expressed stably in CHO cells using [3H]rauwolscine as radioligand
|
Homo sapiens
|
0.42
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Yohimbine dimers exhibiting binding selectivities for human alpha2a- versus alpha2b-adrenergic receptors.
Year : 2000
Volume : 10
Issue : 7
First Page : 627
Last Page : 630
Authors : Zheng W, Lei L, Lalchandani S, Sun G, Feller DR, Miller DD.
Abstract : A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO) cells. All dimers display higher binding selectivities for alpha2a versus alpha2b subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the most potent and alpha2a versus alpha2b-AR selective ligands identified so far.
|
Inhibition of [3H]rauwolscine binding to CHO cells expressing the human Alpha-2A adrenergic receptor
|
None
|
7.5
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Inhibition of [3H]- MK-912 binding against human recombinant Alpha-2A adrenergic receptor
|
None
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.
Year : 1999
Volume : 42
Issue : 25
First Page : 5181
Last Page : 5187
Authors : Belliotti TR, Wustrow DJ, Brink WA, Zoski KT, Shih YH, Whetzel SZ, Georgic LM, Corbin AE, Akunne HC, Heffner TG, Pugsley TA, Wise LD.
Abstract : As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.
|
Binding activity against alpha-1 adrenergic receptor from calf cerebral cortex, using [3H]-prazosin as the radioligand
|
None
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1983
Volume : 26
Issue : 12
First Page : 1696
Last Page : 1701
Authors : Saari WS, Halczenko W, King SW, Huff JR, Guare JP, Hunt CA, Randall WC, Anderson PS, Lotti VJ, Taylor DA.
Abstract : A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.
|
Displacement of [3H]prazosin from calf cerebral cortex alpha-1 adrenergic receptor
|
Bos taurus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.
Year : 1984
Volume : 27
Issue : 9
First Page : 1182
Last Page : 1185
Authors : Saari WS, Halczenko W, Huff JR, Guare JP, Hunt CA, Randall WC, Lotti VJ, Yarbrough GG.
Abstract : A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.
|
Evaluated for its ability to displace [3H]prazosin from alpha-1-Adrenoceptor of calf cerebral cortex
|
None
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin -2-yl)-N- methyl-2-hydroxyethane-sulfonamide: a potent and selective alpha 2-adrenoceptor antagonist.
Year : 1985
Volume : 28
Issue : 12
First Page : 1756
Last Page : 1759
Authors : Huff JR, Anderson PS, Baldwin JJ, Clineschmidt BV, Guare JP, Lotti VJ, Pettibone DJ, Randall WC, Vacca JP.
|
Binding affinity against Alpha-1 adrenergic receptor in rat cerebral cortical membrane, determined using [3H]-prazosin as the radioligand
|
None
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : (8a alpha,12a alpha,13a alpha)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridi ne, a potent and highly selective alpha 2-adrenoceptor antagonist.
Year : 1989
Volume : 32
Issue : 9
First Page : 2034
Last Page : 2036
Authors : Clark RD, Repke DB, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
|
Binding affinity to alpha-1 adrenergic receptor determined by measurement of [3H]prazosin displacement from rat cortical membrane
|
None
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationships of 12-sulfonyl derivatives of 5,8,8a,9,10,11,12,12a,13,13a-decahydro-6H-isoquino[2,1-g][1 ,6] naphthyridines at alpha-adrenoceptors.
Year : 1991
Volume : 34
Issue : 2
First Page : 705
Last Page : 717
Authors : Clark RD, Repke DB, Berger J, Nelson JT, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
Abstract : Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.
|
Binding affinity determined to alpha-1 adrenergic receptor of rat cerebral cortex using [3H]prazosin as radioligand
|
None
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for alpha-adrenoceptors. Differential affinity of imidazolines for the [3H]idazoxan-labeled alpha 2-adrenoceptor vs the [3H]yohimbine-labeled site.
Year : 1990
Volume : 33
Issue : 2
First Page : 596
Last Page : 600
Authors : Clark RD, Berger J, Garg P, Weinhardt KK, Spedding M, Kilpatrick AT, Brown CM, MacKinnon AC.
Abstract : A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquinolin-2- ylmethyl)imidazoline, were found to be selective alpha 2-adrenoceptor ligands on the basis of displacement of [3H]yohimbine from rat cerebral cortical membranes. One compound, 2-[(8-chloro tetrahydroisoquinolin-2-yl)methyl]imidazoline (5m), showed a 36-fold difference in affinity for the [3H]idazoxan-labeled alpha 2-adrenoceptor relative to the [3H]yohimbine-labeled site, which may be evidence for alpha 2-adrenoceptor subtypes.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in canine adipocyte
|
Canis lupus familiaris
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Alpha-2 adrenergic receptor activity was assessed in vitro from the ability to inhibit norepinephrine binding to guinea pig vas deferens
|
Cavia porcellus
|
25.7
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
Antagonistic activity against adrenergic alpha-2 receptor in longitudinal muscle strip of the guinea pig ileum using l-norepinephrine as agonist
|
Rattus norvegicus
|
25.7
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic activity against longitudinal muscle strip of the guinea pig ileum using xylazine as agonist
|
Cavia porcellus
|
43.65
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Alpha-1 adrenergic receptor agonist activity in rat anococcygeus assay
|
Rattus norvegicus
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha-adrenoreceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity.
Year : 1984
Volume : 27
Issue : 5
First Page : 570
Last Page : 576
Authors : Chapleo CB, Myers PL, Butler RC, Davis JA, Doxey JC, Higgins SD, Myers M, Roach AG, Smith CF, Stillings MR.
Abstract : Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in hamster adipocyte
|
Cricetulus griseus
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Inhibition of [3H]p-aminoclonidine (PAC) binding to alpha-2 adrenergic receptor of purified human platelet plasma membranes
|
None
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Radioiodinated p-iodoclonidine: a high-affinity probe for the alpha 2-adrenergic receptor.
Year : 1987
Volume : 30
Issue : 7
First Page : 1241
Last Page : 1244
Authors : Van Dort M, Neubig R, Counsell RE.
Abstract : The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding assays conducted with purified human platelet plasma membrane fractions. For the synthesis of radioiodinated PIC the triazene intermediate 11 was synthesized from 2,6-dichloro-4-nitroaniline in five synthetic steps. Acid-catalyzed decomposition of 11 with no-carrier-added Na125I afforded high specific activity [125I]PIC. In view of its high affinity for the alpha 2-adrenergic receptor, [125I]PIC is a potentially useful probe for studies in adrenergic pharmacology.
|
Binding affinity against human alpha 2b-adrenergic receptor expressed stably in CHO cells using [3H]rauwolscine as radioligand
|
Homo sapiens
|
2.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Yohimbine dimers exhibiting binding selectivities for human alpha2a- versus alpha2b-adrenergic receptors.
Year : 2000
Volume : 10
Issue : 7
First Page : 627
Last Page : 630
Authors : Zheng W, Lei L, Lalchandani S, Sun G, Feller DR, Miller DD.
Abstract : A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO) cells. All dimers display higher binding selectivities for alpha2a versus alpha2b subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the most potent and alpha2a versus alpha2b-AR selective ligands identified so far.
|
Inhibition of [3H]rauwolscine binding to CHO cells expressing the human Alpha-2B adrenergic receptor
|
None
|
4.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Antagonistic activity against postsynaptic alpha-1 adrenergic receptor in rabbit pulmonary artery using l-norepinephrine as agonist
|
Oryctolagus cuniculus
|
147.91
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in HT-29 cell
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in alpha2C10
|
None
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in alpha2C2
|
None
|
4.1
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in human adipocyte
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in human platelet
|
None
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in rat adipocyte
|
None
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in Malpha-10H (mouse)
|
None
|
54.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in Malpha2-4H (mouse)
|
None
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in NG-108 cell
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Inhibition of [3H]- Yohimbine binding against rat kidney cortex Alpha-2B adrenergic receptor
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.
Year : 1999
Volume : 42
Issue : 25
First Page : 5181
Last Page : 5187
Authors : Belliotti TR, Wustrow DJ, Brink WA, Zoski KT, Shih YH, Whetzel SZ, Georgic LM, Corbin AE, Akunne HC, Heffner TG, Pugsley TA, Wise LD.
Abstract : As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.
|
Inhibition of [3H]rauwolscine to CHO cells expressing the human Alpha-2C adrenergic receptor
|
None
|
2.3
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Inhibition of specific [3H]prazosin binding (0.2 nM) to rat brain membranes alpha-1 adrenergic receptor
|
Oryctolagus cuniculus
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Inhibition of phenylephrine-induced contraction of the rabbit aorta as a measure of functional alpha-1-adrenoceptor antagonism
|
Oryctolagus cuniculus
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : (8a alpha,12a alpha,13a alpha)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridi ne, a potent and highly selective alpha 2-adrenoceptor antagonist.
Year : 1989
Volume : 32
Issue : 9
First Page : 2034
Last Page : 2036
Authors : Clark RD, Repke DB, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
|
Alpha-2 adrenergic receptor agonist activity in mouse vas deferens relative to clonidine
|
Mus musculus
|
10.47
nM
|
|
Journal : J. Med. Chem.
Title : Alpha-adrenoreceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity.
Year : 1984
Volume : 27
Issue : 5
First Page : 570
Last Page : 576
Authors : Chapleo CB, Myers PL, Butler RC, Davis JA, Doxey JC, Higgins SD, Myers M, Roach AG, Smith CF, Stillings MR.
Abstract : Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in OK cell
|
opossum
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in opossum kidney
|
opossum
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in porcine alpha2-clone
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]-yohimbine to Alpha-2 adrenergic receptor in rabbit adipocyte
|
Oryctolagus cuniculus
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Alpha-2 adrenergic receptor pA2 value against clonidine in vitro experiment in rat vas deferens
|
None
|
7.244
nM
|
|
Journal : J. Med. Chem.
Title : alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.
Year : 1983
Volume : 26
Issue : 6
First Page : 823
Last Page : 831
Authors : Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF.
Abstract : The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.
|
Alpha-1-adrenolytic activity was assessed in vitro from the ability to inhibit clonidine binding to rat aorta preparation
|
None
|
346.74
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
Alpha-2 adrenergic receptor activity was assessed from the ability to inhibit [3H]yohimbine binding to rat cerebral cortex preparation
|
None
|
9.1
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
Binding affinity towards rat Alpha-2 adrenergic receptor was evaluated using [3H]- yohimbine as radioligand
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on the 5-HT(1A) receptor affinity of 1-phenyl-4-[omega-(alpha- or beta-tetralinyl)alkyl]piperazines. 4.
Year : 1996
Volume : 39
Issue : 25
First Page : 4928
Last Page : 4934
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis of 1-phenylpiperazines, linked in the alpha or beta position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT(2A), D-1, D-2, alpha1, and alpha2 receptors along with SAR studies on the 5-HT(1A) receptor are reported. Several changes have been carried out on previous structures of type 2, by inserting the alkyl chain with variable length in the alpha or beta position of the tetralin moiety and by changing the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest affinity (IC50 = 0.50 nM) and selectivity for the 5-HT(1A) receptor were showed by 1-phenylpiperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the omega position.
|
Binding affinity against Alpha-2 adrenergic receptor in rat brain membrane using [3H]yohimbine as radioligand
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-aryl-4-[(1-tetralinyl)alkyl]piperazines: alkylamido and alkylamino derivatives. Synthesis, 5-HT1A receptor affinity, and selectivity. 3.
Year : 1996
Volume : 39
Issue : 16
First Page : 3195
Last Page : 3202
Authors : Perrone R, Berardi F, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis and binding profile on 5-HT1A, 5-HT2, D-1, D-2, alpha 1, and alpha 2 receptors of the N-4 long-chain arylpiperazines 22-40 are reported, where an amino or amido function is inserted into the intermediate chain linked to the alpha position of the tetralin nucleus. Unlike the buspirone analogues, for the amido derivatives studied in this paper, the terminal amide function of long-chain piperazines is not important for 5-HT1A receptor affinity binding, and its removal yields high-affinity 5-HT1A receptor agents.
|
In vitro inhibition of binding of [3H]-RX-821002 to alpha-2 adrenergic receptor site in rat brain membranes.
|
None
|
67.0
nM
|
|
Journal : J. Med. Chem.
Title : New substituted 1-(2,3-dihydrobenzo[1, 4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with alpha(2)-adrenoceptor antagonist activity.
Year : 2000
Volume : 43
Issue : 20
First Page : 3653
Last Page : 3664
Authors : Mayer P, Brunel P, Chaplain C, Piedecoq C, Calmel F, Schambel P, Chopin P, Wurch T, Pauwels PJ, Marien M, Vidaluc JL, Imbert T.
Abstract : The emergence of a novel theory concerning the role of noradrenaline in the progression and the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases has provided a new impetus toward the discovery of novel compounds acting at alpha(2)-adrenoceptors. A series of substituted 1-(2, 3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series of compounds proved to be potent alpha(2)-adrenoceptor antagonists with good selectivity versus alpha(1)-adrenergic and D(2)-dopamine receptors. Particular emphasis is given to compound 33g which displays potent alpha(2)-adrenoceptor binding affinity in vitro and central effects in vivo following oral administration.
|
Binding affinity against alpha-2 adrenergic receptor was determined by the displacement of [3H]prazosin from rat brain cortical membranes
|
None
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
Binding affinity against Alpha-1B adrenergic receptor from hamster clones.
|
hamster
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Inhibition of [3H]prazosin binding to human Alpha-1B adrenergic receptor expressed in CHO cells
|
Homo sapiens
|
966.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in RG20 (rat)
|
None
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in RGlO (rat)
|
None
|
2.4
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in RIN-m5F cell
|
None
|
104.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in RNG (rat)
|
None
|
8.7
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]-yohimbine to Alpha-2 adrenergic receptor in alpha-2 C4
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in neonatal rat lung
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in rat enterocyte
|
None
|
54.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was evaluated for inhibition of binding of [3H]yohimbine to Alpha-2 adrenergic receptor in rat kidney
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity against Alpha-1B adrenergic receptor from human clone
|
Homo sapiens
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Evaluated for its ability to displace [3H]rauwolscine from alpha-2 adrenergic receptor of rat cerebral cortex
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin -2-yl)-N- methyl-2-hydroxyethane-sulfonamide: a potent and selective alpha 2-adrenoceptor antagonist.
Year : 1985
Volume : 28
Issue : 12
First Page : 1756
Last Page : 1759
Authors : Huff JR, Anderson PS, Baldwin JJ, Clineschmidt BV, Guare JP, Lotti VJ, Pettibone DJ, Randall WC, Vacca JP.
|
In vitro binding affinity was measured as the inhibition of [3H]clonidine binding to alpha-2 adrenergic receptor of rat cortical membranes
|
None
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Year : 1986
Volume : 29
Issue : 8
First Page : 1394
Last Page : 1398
Authors : Guérémy C, Audiau F, Renault C, Benavides J, Uzan A, Le Fur G.
Abstract : A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
|
Inhibition of [3H]idazoxan binding to alpha-2 adrenergic receptor of rat cortical membranes
|
Rattus norvegicus
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Year : 1986
Volume : 29
Issue : 8
First Page : 1394
Last Page : 1398
Authors : Guérémy C, Audiau F, Renault C, Benavides J, Uzan A, Le Fur G.
Abstract : A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
|
In Vitro reversal of inhibitory effect of UK - 14304 on the contractile response of guinea pig ileum to field stimulation.
|
Cavia porcellus
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationships of 12-sulfonyl derivatives of 5,8,8a,9,10,11,12,12a,13,13a-decahydro-6H-isoquino[2,1-g][1 ,6] naphthyridines at alpha-adrenoceptors.
Year : 1991
Volume : 34
Issue : 2
First Page : 705
Last Page : 717
Authors : Clark RD, Repke DB, Berger J, Nelson JT, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
Abstract : Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.
|
Inhibition of 1'-hydroxybufuralol formation by human liver microsomes
|
Homo sapiens
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of 1'-hydroxybufuralol formation by human liver microsomes
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of 1'-hydroxybufuralol formation by human liver microsomes
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of 1'-hydroxybufuralol formation by human liver microsomes
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibitory effect on Bufuralol 1'-hydroxylation by human liver microsomes (Ki = apparent inhibition constant)
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of partially purified cytochrome P450 2D6 1'-hydroxybufuralol formation
|
Homo sapiens
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of specific [3H]clonidine binding (0.4 nM) to rat brain membranes alpha2 adrenoceptor
|
None
|
165.0
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Inhibition constant on radiolabeled [125 I] FIDA2 binding to rat striatal membranes
|
Rattus norvegicus
|
505.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorinated and iodinated dopamine agents: D2 imaging agents for PET and SPECT.
Year : 1993
Volume : 36
Issue : 2
First Page : 221
Last Page : 228
Authors : Chumpradit S, Kung MP, Billings J, Mach R, Kung HF.
Abstract : A novel series of dual-labeling D2 dopamine agents (labeled with either 18F or 123I for PET or SPECT imaging, respectively) was investigated. Two desired fluorinated and iodinated dopamine agents, FIDA1, (S)-(-)-2-(2-fluoroethoxy)-5-iodo-3-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]-benzamide, and FIDA2, (R)-(+)-2,3-dimethoxy-5-iodo-N-[(1-(4'-fluorobenzyl)-2- pyrrolidinyl)-methyl]benzamide, were synthesized. Both compounds displayed high affinity to the D2 receptor of rat striatal membrane preparations (Kd = 0.13 and 0.02 nM for FIDA1 and FIDA2, respectively). The biodistribution study in rats exhibited high localization in the striata of the brain with the striatum/cerebellum ratio reaching 29.3 and 13.1 at 1 h post iv injection for FIDA1 and FIDA2, respectively. Imaging studies with [18F]- and [123I]FIDA2 in monkeys, with PET and SPECT, respectively, showed comparable high selective striatal uptake. These results suggest that they are potentially useful D2 dopamine receptor imaging agents for PET and SPECT.
|
In vivo antagonist activity against B-HT 933-induced Alpha-2 adrenergic receptor-mediated vasoconstriction in pithed normotensive rats
|
Rattus norvegicus
|
147.91
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Tested for antagonism of clonidine in the field-stimulated rat vas deferens.
|
Rattus norvegicus
|
22.39
nM
|
|
Journal : J. Med. Chem.
Title : N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin -2-yl)-N- methyl-2-hydroxyethane-sulfonamide: a potent and selective alpha 2-adrenoceptor antagonist.
Year : 1985
Volume : 28
Issue : 12
First Page : 1756
Last Page : 1759
Authors : Huff JR, Anderson PS, Baldwin JJ, Clineschmidt BV, Guare JP, Lotti VJ, Pettibone DJ, Randall WC, Vacca JP.
|
Tested for antagonism of methoxamine in the field-stimulated rat vas deferens.
|
Rattus norvegicus
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin -2-yl)-N- methyl-2-hydroxyethane-sulfonamide: a potent and selective alpha 2-adrenoceptor antagonist.
Year : 1985
Volume : 28
Issue : 12
First Page : 1756
Last Page : 1759
Authors : Huff JR, Anderson PS, Baldwin JJ, Clineschmidt BV, Guare JP, Lotti VJ, Pettibone DJ, Randall WC, Vacca JP.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
25.6
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Inhibition of [3H]nitrendipine binding to membrane homogenates of rat cardiac muscle.
|
Rattus norvegicus
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Ability to displace [3H]clonidine from alpha-2 adrenergic receptor in rat brain homogenates in vitro
|
None
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant properties of novel 2-substituted 4,5-dihydro-1H-imidazole derivatives.
Year : 1987
Volume : 30
Issue : 8
First Page : 1482
Last Page : 1489
Authors : Wentland MP, Bailey DM, Alexander EJ, Castaldi MJ, Ferrari RA, Haubrich DR, Luttinger DA, Perrone MH.
Abstract : A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
|
In vitro antagonistic activity against alpha-2 adrenergic receptor in isolated electrically stimulated rat vas deferens (clonidine-induced decrease in twitch height)
|
None
|
12.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant properties of novel 2-substituted 4,5-dihydro-1H-imidazole derivatives.
Year : 1987
Volume : 30
Issue : 8
First Page : 1482
Last Page : 1489
Authors : Wentland MP, Bailey DM, Alexander EJ, Castaldi MJ, Ferrari RA, Haubrich DR, Luttinger DA, Perrone MH.
Abstract : A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
|
Ability to reversal of inhibitory effects of UK-14304 on the contraction of guinea pig ileum as a measure of alpha-2-adrenoceptor antagonism
|
Cavia porcellus
|
31.62
nM
|
|
Journal : J. Med. Chem.
Title : (8a alpha,12a alpha,13a alpha)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridi ne, a potent and highly selective alpha 2-adrenoceptor antagonist.
Year : 1989
Volume : 32
Issue : 9
First Page : 2034
Last Page : 2036
Authors : Clark RD, Repke DB, Kilpatrick AT, Brown CM, MacKinnon AC, Clague RU, Spedding M.
|
Binding affinity against alpha-2 adrenergic receptor was determined by the displacement of [3H]clonidine from rat brain cortical membranes
|
None
|
84.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
Binding affinity for cytochrome P450 2D6
|
None
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition.
Year : 2004
Volume : 47
Issue : 22
First Page : 5340
Last Page : 5346
Authors : Kemp CA, Flanagan JU, van Eldik AJ, Maréchal JD, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ.
Abstract : There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.
|
In vitro binding affinity towards alpha-2a adrenergic receptor
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological studies of yohimbine derivatives on human alpha2C-adrenergic receptors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2758
Last Page : 2760
Authors : Mustafa SM, Bavadekar SA, Ma G, Moore BM, Feller DR, Miller DD.
Abstract : A series of yohimbine derivatives was synthesized and evaluated for binding affinity at the human alpha(2C)-adrenergic receptors expressed in Chinese hamster ovary cells. It has been found that compound 5 shows a higher affinity for alpha(2C)-AR than the parent compound yohimbine 1, thereby illustrating that the nature of the linkers affect binding potencies on these receptors.
|
In vitro binding affinity towards alpha-2b adrenergic receptor
|
Homo sapiens
|
7.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological studies of yohimbine derivatives on human alpha2C-adrenergic receptors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2758
Last Page : 2760
Authors : Mustafa SM, Bavadekar SA, Ma G, Moore BM, Feller DR, Miller DD.
Abstract : A series of yohimbine derivatives was synthesized and evaluated for binding affinity at the human alpha(2C)-adrenergic receptors expressed in Chinese hamster ovary cells. It has been found that compound 5 shows a higher affinity for alpha(2C)-AR than the parent compound yohimbine 1, thereby illustrating that the nature of the linkers affect binding potencies on these receptors.
|
In vitro binding affinity measured by displacement of [3H]rauwolscine from alpha-2c adrenergic receptor expressed in CHO cells in presence of phentolamine
|
Homo sapiens
|
0.88
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological studies of yohimbine derivatives on human alpha2C-adrenergic receptors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2758
Last Page : 2760
Authors : Mustafa SM, Bavadekar SA, Ma G, Moore BM, Feller DR, Miller DD.
Abstract : A series of yohimbine derivatives was synthesized and evaluated for binding affinity at the human alpha(2C)-adrenergic receptors expressed in Chinese hamster ovary cells. It has been found that compound 5 shows a higher affinity for alpha(2C)-AR than the parent compound yohimbine 1, thereby illustrating that the nature of the linkers affect binding potencies on these receptors.
|
Inhibitory concentration against cytochrome P450 2D6
|
None
|
8.4
nM
|
|
Journal : J. Med. Chem.
Title : Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition.
Year : 2004
Volume : 47
Issue : 22
First Page : 5340
Last Page : 5346
Authors : Kemp CA, Flanagan JU, van Eldik AJ, Maréchal JD, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ.
Abstract : There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.
|
Percent inhibition against Alpha-2 adrenergic receptor at 1 uM
|
Homo sapiens
|
95.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.
Year : 2005
Volume : 48
Issue : 22
First Page : 6887
Last Page : 6896
Authors : Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G.
Abstract : Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
|
Inhibition of alpha 2 adrenergic receptor
|
None
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4150
Last Page : 4169
Authors : Grice CA, Tays KL, Savall BM, Wei J, Butler CR, Axe FU, Bembenek SD, Fourie AM, Dunford PJ, Lundeen K, Coles F, Xue X, Riley JP, Williams KN, Karlsson L, Edwards JP.
Abstract : LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
|
Displacement of radiolabeled yohimbine from adrenergic alpha2 receptor
|
None
|
100.0
nM
|
|
Displacement of radiolabeled yohimbine from adrenergic alpha2 receptor
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Year : 2008
Volume : 51
Issue : 22
First Page : 7094
Last Page : 7098
Authors : Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR, Strakhova MI, Vortherms TA, Wakefield BD, Wetter JM, Witte DG, Honore P, Esbenshade TA, Brioni JD, Cowart MD.
Abstract : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
|
Displacement of [3H]MK912 from human recombinant adrenergic alpha2A receptor expressed in Sf9 cells
|
Homo sapiens
|
8.5
nM
|
|
Journal : J. Nat. Prod.
Title : Alkaloids from Eschscholzia californica and their capacity to inhibit binding of [3H]8-Hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A receptors in Vitro.
Year : 2006
Volume : 69
Issue : 3
First Page : 432
Last Page : 435
Authors : Gafner S, Dietz BM, McPhail KL, Scott IM, Glinski JA, Russell FE, McCollom MM, Budzinski JW, Foster BC, Bergeron C, Rhyu MR, Bolton JL.
Abstract : A 70% ethanol extract of California poppy (Eschscholzia californica) was able to bind to 5-HT(1A) and 5-HT(7) receptors at 100 mug/mL. The subsequent isolation procedure yielded the known alkaloids californidine (1), escholtzine (2), N-methyllaurotetanine (3), caryachine (4), and O-methylcaryachine (5), along with a new pavine alkaloid, 6S,12S-neocaryachine-7-O-methyl ether N-metho salt (7). The structure of 7 was determined by spectroscopic data interpretation, while the absolute stereochemistry was determined by means of circular dichroism. From the results obtained from the radioligand-binding assay of the pure compounds, including the commercially available protopine (6), it was evident that the activity on the 5-HT(1A) receptor was at least partly due to the presence of the aporphine alkaloid 3, which showed the highest inhibition of [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin ([(3)H]8-OH-DPAT) binding with an EC(50) value of 155 nM and a K(i) of 85 nM.
|
Inhibition of rat alpha2 adrenoceptor
|
Rattus norvegicus
|
58.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
Displacement of [3H]RX821002 from adrenergic alpha2 receptor
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.
Year : 2011
Volume : 54
Issue : 15
First Page : 5320
Last Page : 5334
Authors : Dolusić E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, Pochet L, Van den Eynde B, Masereel B, Wouters J, Frédérick R.
Abstract : Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT1A radioligand binding (ligand: [3H] 8-OH-DPAT)
|
None
|
126.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT1A radioligand binding (ligand: [3H] 8-OH-DPAT)
|
None
|
72.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
500.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
658.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
498.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
6.151
nM
|
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
2.307
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
17.0
nM
|
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
7.947
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
36.0
nM
|
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
5.162
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
74.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
47.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT6 radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
784.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
687.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
157.0
nM
|
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
105.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Binding affinity to adrenergic alpha2 receptor (unknown origin) by radioligand displacement assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
Year : 2013
Volume : 21
Issue : 10
First Page : 2764
Last Page : 2771
Authors : Veinberg G, Vorona M, Zvejniece L, Vilskersts R, Vavers E, Liepinsh E, Kazoka H, Belyakov S, Mishnev A, Kuznecovs J, Vikainis S, Orlova N, Lebedev A, Ponomaryov Y, Dambrova M.
Abstract : Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
|
Displacement of [3H]MK912 from human recombinant alpha2A adrenergic receptor expressed in Sf9 cells after 60 mins
|
Homo sapiens
|
3.1
nM
|
|
Displacement of [3H]MK912 from human recombinant alpha2A adrenergic receptor expressed in Sf9 cells after 60 mins
|
Homo sapiens
|
8.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]MK912 from human recombinant alpha2A adrenergic receptor expressed in Sf9 cells at 10 uM after 60 mins relative to control
|
Homo sapiens
|
-5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Binding affinity to adrenergic alpha2 receptor (unknown origin) by radioligand displacement assay
|
Homo sapiens
|
25.0
nM
|
|
Binding affinity to adrenergic alpha2 receptor (unknown origin) by radioligand displacement assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Displacement of [125I]Clonidine from adrenergic alpha2B receptor (unknown origin)
|
Homo sapiens
|
28.84
nM
|
|
Displacement of [125I]Clonidine from adrenergic alpha2B receptor (unknown origin)
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and comparative receptor binding affinities of novel, isomeric pyridoindolobenzazepine scaffolds.
Year : 2014
Volume : 24
Issue : 2
First Page : 576
Last Page : 579
Authors : Rajagopalan R, Bandyopadhyaya A, Rajagopalan DR, Rajagopalan P.
Abstract : Compounds 7, 8, and 9, derived from the novel scaffolds 3, 5, and 6, were synthesized and evaluated in vitro. The b,c→c,d shift of the E-phenyl ring resulted in a large decrease (ca. 20- to 1000-fold) in binding to the 5-HT2A, 5-HT2C and H2, receptors, and a modest decrease (ca. 10- to 20-fold) in binding to the 5-HT5A, D2, D5, and α1D, receptors. The b,c→d,e shift resulted in a large decrease in binding to the 5-HT1D, 5-HT2C, 5-HT6, and H1 receptors, a modest decrease in binding to 5-HT1A, 5-HT5A and D2, D5, α2B, and H2 receptors, and a large increase in affinity to the 5-HT3, 5-HT6, and σ1 receptors.
|
Displacement of [3H]RX821002 from human recombinant alpha2C adrenoceptor expressed in CHO cells
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia.
Year : 2014
Volume : 57
Issue : 11
First Page : 4543
Last Page : 4557
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski M, Mitka K, Jaśkowska J, Kowalski P, Kazek G, Siwek A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
|
Displacement of [3H]RX-821002 from human adrenergic alpha2C receptor expressed in CHO cells
|
Homo sapiens
|
0.5
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.
|
Displacement of [3H]RX 821002 from rat cerebral cortex Alpha-2 adrenergic receptor
|
Rattus norvegicus
|
96.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.
Year : 2016
Volume : 24
Issue : 8
First Page : 1793
Last Page : 1810
Authors : Waszkielewicz AM, Gunia-Krzyżak A, Powroźnik B, Słoczyńska K, Pękala E, Walczak M, Bednarski M, Żesławska E, Nitek W, Marona H.
Abstract : A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.
|
Displacement of [3H]RX 821002 from rat cerebral cortex alpha-2 adrenergic receptor measured after 60 mins by scintillation counting method
|
Rattus norvegicus
|
96.0
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Year : 2017
Volume : 25
Issue : 2
First Page : 471
Last Page : 482
Authors : Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H.
Abstract : A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
|
Antagonist activity at human CCR8 expressed in CHOK1 cells assessed as inhibition in CCL1-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by CCL1 addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gs/Gi/o-coupled CHRM4 expressed in CHOK1 cells assessed as inhibition in acetylcholine-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by acetylcholine addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
4.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gi/o-coupled CNR1 expressed in CHOK1 cells assessed as inhibition in CP55940-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by CP55940 addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
35.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gi/o-coupled CNR2 expressed in CHOK1 cells assessed as inhibition in CP55940-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by CP55940 addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gi/o-coupled CXCR4 expressed in mouse C2C12 cells assessed as inhibition in CXCL12-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by CXCL12 addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
21.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gi/o-coupled DRD2L expressed in CHOK1 cells assessed as inhibition in dopamine-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by dopamine addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
102.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gi/o-coupled FPR1 expressed in CHOK1 cells assessed as inhibition in WKYMVm-NH2-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by WKYMVm-NH2 addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
-6.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human GPR119 assessed as inhibition in oleoylethanolamide-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by oleoylethanolamide addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
8.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gq-coupled HCRTR2 expressed in CHOK1 cells assessed as inhibition in Orexin A-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by Orexin A addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
9.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gq-coupled HRH1 expressed in CHOK1 cells assessed as inhibition in histamine-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by histamine addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
30.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gq-coupled NPSR1b expressed in human U2OS cells assessed as inhibition in neuropeptide S-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by neuropeptide S addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
-3.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gq-coupled PRLHR expressed in CHOK1 cells assessed as inhibition in prolactin releasing peptide (1 to 31)-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by prolactin releasing peptide (1 to 31) addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Antagonist activity at human Gs-coupled PTGIR assessed as inhibition in beraprost-induced beta-arrestin 2 recruitment at 20 uM incubated for 30 mins followed by beraprost- addition and measured after 90 or 180 mins by pathhunter beta-arrestin assay relative to control
|
Homo sapiens
|
8.0
%
|
|
Journal : J Med Chem
Title : Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.
Year : 2020
Volume : 63
Issue : 10
First Page : 5119
Last Page : 5138
Authors : Norwood VM, Brice-Tutt AC, Eans SO, Stacy HM, Shi G, Ratnayake R, Rocca JR, Abboud KA, Li C, Luesch H, McLaughlin JP, Huigens RW.
Abstract : Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
|
Displacement of [3H]RX 821002 from human recombinant adrenergic alpha-2A receptor expressed in CHO cell membranes incubated for 60 mins
|
Homo sapiens
|
3.13
nM
|
|
Journal : J Med Chem
Title : Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids.
Year : 2020
Volume : 63
Issue : 1
First Page : 433
Last Page : 439
Authors : Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, Chear NJ, Ramanathan S, Sharma A, León F, Hiranita T, Avery BA, McMahon LR, McCurdy CR.
Abstract : Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in <i>Mitragyna speciosa</i> (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
|
Displacement of [3H]RX 821002 from human recombinant adrenergic alpha-2B receptor expressed in CHO cell membranes incubated for 60 mins
|
Homo sapiens
|
1.16
nM
|
|
Journal : J Med Chem
Title : Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids.
Year : 2020
Volume : 63
Issue : 1
First Page : 433
Last Page : 439
Authors : Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, Chear NJ, Ramanathan S, Sharma A, León F, Hiranita T, Avery BA, McMahon LR, McCurdy CR.
Abstract : Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in <i>Mitragyna speciosa</i> (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
|
Displacement of [3H]RX 821002 from human recombinant adrenergic alpha-2C receptor expressed in CHO cell membranes incubated for 60 mins
|
Homo sapiens
|
0.8
nM
|
|
Journal : J Med Chem
Title : Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids.
Year : 2020
Volume : 63
Issue : 1
First Page : 433
Last Page : 439
Authors : Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, Chear NJ, Ramanathan S, Sharma A, León F, Hiranita T, Avery BA, McMahon LR, McCurdy CR.
Abstract : Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in <i>Mitragyna speciosa</i> (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
|
Antagonist activity at human ADRA1B expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
90.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human ADRA2B expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
107.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human AVPR2 at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
-1.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human CCR3 expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
-13.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human CCR8 expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human CX3CR1 expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
22.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human CXCR4 expressed in mouse C2C12 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
21.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human DRD2L expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
102.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human FSHR expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
4.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at HTR1B in human U2OS cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at HTR2C in human U2OS cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at NPSR1B in human U2OS cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
-3.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human OXTR expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
|
Antagonist activity at human PRLHR expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
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Antagonist activity at human ADRA2A expressed in CHO-K1 cells at 20 uM by PathHunter beta-arrestin assay relative to control
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Homo sapiens
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92.0
%
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Journal : Bioorg Med Chem
Title : Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Year : 2020
Volume : 28
Issue : 14
First Page : 115546
Last Page : 115546
Authors : Paciaroni NG,Norwood VM,Ratnayake R,Luesch H,Huigens RW
Abstract : G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal systems. The overarching goal of our ring distortion approach is to re-program the biological activity of select natural products and identify new compounds of importance to the treatment of disease, such as cancer. Described herein are the results from biological screens of diverse small molecules derived from the indole alkaloid yohimbine against a panel of GPCRs involved in various diseases. Several analogues displayed highly differential antagonistic activities across the GPCRs tested. We highlight the re-programmed profile of one analogue, Y7g, which exhibited selective antagonistic activities against AVPR2 (IC = 459 nM) and OXTR (IC = 1.16 µM). The activity profile of Y7g could correlate its HIF-dependent anti-cancer activity to its GPCR antagonism since these receptors are known to be upregulated in hypoxic cellular environments. Our findings demonstrate that the ring distortion of yohimbine can lead to the identification of new compounds capable of interacting with distinct cancer-relevant targets.
