|
Displacement of [3H]clonidine from adrenergic alpha 2 receptor of rat cerebral cortical membranes
|
Rattus norvegicus
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses of 2,5- and 2,6-difluoronorepinephrine, 2,5-difluoroepinephrine, and 2,6-difluorophenylephrine: effect of disubstitution with fluorine on adrenergic activity.
Year : 1993
Volume : 36
Issue : 24
First Page : 3947
Last Page : 3955
Authors : Chen GT, King M, Gusovsky F, Creveling CR, Daly JW, Chen BH, Nie JY, Kirk KL.
Abstract : Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both alpha- and beta-adrenergic receptors. These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases alpha-adrenergic activity whereas 6-fluoro substitution decreases beta-adrenergic activity.
|
Binding affinity against alpha 2-Adrenergic receptor in guinea pig cerebral cortical membranes by displacement of [3H]clonidine
|
Cavia porcellus
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic activities of ring-fluorinated epinephrines.
Year : 1988
Volume : 31
Issue : 10
First Page : 1972
Last Page : 1977
Authors : Adejare A, Gusovsky F, Padgett W, Creveling CR, Daly JW, Kirk KL.
Abstract : The study of chemical and biological effects of fluorine substitution on the aromatic ring of catecholamines has now been extended to epinephrine (Epi). 2- and 6-fluoroepinephrines (2-FEpi and 6-FEpi) have been synthesized. Fluorine substitution on the 2- or 6-carbon of the aromatic ring alters the selectivity of epinephrine toward alpha- and beta-adrenergic receptors, similar in manner to the change in selectivity seen with norepinephrine (NE). Thus, 2-FEpi is a relatively selective beta-adrenergic ligand, while 6-FEpi is a relatively selective alpha-adrenergic ligand. Fluorine substitution of Epi also can markedly increase potency at either alpha- or beta-adrenergic receptors.
|
Binding affinity against Alpha adrenergic receptor using [3H]dihydroergocryptine radioligand in rat brain homogenate
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and adrenoceptor affinity of some highly polar beta-substituted catecholamines.
Year : 1981
Volume : 24
Issue : 10
First Page : 1258
Last Page : 1260
Authors : Henkel JG, Sikand N, Makriyannis A, Gianutsos G.
Abstract : In order to assess the potential for sympathomimetic or sympatholytic activity within the series of catecholamine beta-sulfonates 3a-c, alpha- and beta-adrenoceptor binding affinities were determined using rat brain homogenate preparations. Furthermore, their potential for indirect activity was assessed by measurement of blockade of norepinephrine uptake into rat synaptosomal preparations. Activity was uniformly low or nonexistent throughout the series. The possibility of unfavorable solution conformational distribution within the series was investigated by examination of the side chain vicinal 1H NMR coupling constants, but no differences that could account for the lack of affinity were found. The observed behavior may be due to receptor intolerance of the bulky beta-sulfonate substituent or an electronic mismatch in which normal H bonding is significantly altered.
|
Displacement of [3H]clonidine from Alpha-2 adrenergic receptor of rat brain membranes
|
Rattus norvegicus
|
17.0
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.
|
The compound was evaluated for the binding affinity towards alpha-2 adrenergic receptor from rat cortex
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.
Year : 1986
Volume : 29
Issue : 4
First Page : 463
Last Page : 467
Authors : DeBernardis JF, Kyncl JJ, Basha FZ, Arendsen DL, Martin YC, Winn M, Kerkman DJ.
Abstract : The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).
|
The compound was evaluated for the inhibition of [3H]prazosin binding to alpha-1 adrenergic receptor from rat liver
|
None
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.
Year : 1986
Volume : 29
Issue : 4
First Page : 463
Last Page : 467
Authors : DeBernardis JF, Kyncl JJ, Basha FZ, Arendsen DL, Martin YC, Winn M, Kerkman DJ.
Abstract : The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).
|
In vitro agonist potency towards Alpha-1D adrenergic receptor in rat aorta
|
None
|
12.02
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.
Year : 1996
Volume : 39
Issue : 20
First Page : 4116
Last Page : 4119
Authors : Meyer MD, Altenbach RJ, Hancock AA, Buckner SA, Knepper SM, Kerwin JF.
Abstract : The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.
|
Binding affinity towards rat clonal Alpha-1D adrenergic receptor
|
None
|
22.39
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.
Year : 1996
Volume : 39
Issue : 20
First Page : 4116
Last Page : 4119
Authors : Meyer MD, Altenbach RJ, Hancock AA, Buckner SA, Knepper SM, Kerwin JF.
Abstract : The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.
|
Tested for binding affinity against alpha-2 adrenergic receptor in rat brain using [3H]- rauwolscine as radioligand
|
None
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
Year : 1993
Volume : 36
Issue : 21
First Page : 3077
Last Page : 3086
Authors : Macchia B, Balsamo A, Breschi MC, Chiellini G, Lapucci A, Macchia M, Manera C, Martinelli A, Martini C, Scatizzi R.
Abstract : In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
|
Binding affinity for human Alpha-2A adrenergic receptor
|
Homo sapiens
|
66.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Effective dose for contraction of reserpine-pretreated guinea pig aorta.
|
None
|
112.0
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.
|
Effective dose for inhibition of neurotransmission in field-stimulated, reserpine-pretreated guinea pig ileum.
|
None
|
30.0
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 for rat Alpha-2B adrenergic receptor
|
Rattus norvegicus
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Alpha-1 adrenergic receptor activation causing vasoconstriction in the isolated rabbit ear artery
|
Oryctolagus cuniculus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha-Adrenergic agents. 2. Synthesis and alpha 1-agonist activity of 2-aminotetralins.
Year : 1982
Volume : 25
Issue : 2
First Page : 136
Last Page : 141
Authors : DeMarinis RM, Shah DH, Hall RF, Hieble JP, Pendleton RG.
Abstract : Substituted 2-aminotetralins are potent, selective, direct-acting agonists at postjunctional alpha 1 receptors. Within this series, substituent alterations on the ring, as well as on the nitrogen, change the potency of compounds by over three orders of magnitude (EC50 = 12 to greater than 10 000 nM). It has been demonstrated experimentally that substitution at both the 5 and 8 positions of the aromatic ring produces optimum agonist potency. Removal of either substituent results in a loss of potency and efficacy relative to norepinephrine. Substitution at positions 6 and/or 7 is generally detrimental to activity. Methyl, ethyl, or dimethyl substitution on nitrogen is compatible with high agonist potency, while substitution with larger groups is not. The most potent agonist in this series is 5-(thiomethyl)-8-methoxy-2-aminotetralin, which has an EC50 of 12 nM.
|
Binding affinity for human Alpha-2C adrenergic receptor
|
Homo sapiens
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Effective dose for contraction of rabbit aorta.
|
None
|
6.6
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.
|
Effective dose for contraction of rat aorta.
|
None
|
1.2
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.
|
Effective dose for on contraction of rat aorta.
|
None
|
200.0
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.
|
Tested for binding affinity against alpha-1 adrenergic receptor in rat brain using [3H]-Prazosin as radioligand
|
None
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
Year : 1993
Volume : 36
Issue : 21
First Page : 3077
Last Page : 3086
Authors : Macchia B, Balsamo A, Breschi MC, Chiellini G, Lapucci A, Macchia M, Manera C, Martinelli A, Martini C, Scatizzi R.
Abstract : In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
|
Binding affinity towards bovine clonal Alpha-1A adrenergic receptor
|
None
|
446.68
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.
Year : 1996
Volume : 39
Issue : 20
First Page : 4116
Last Page : 4119
Authors : Meyer MD, Altenbach RJ, Hancock AA, Buckner SA, Knepper SM, Kerwin JF.
Abstract : The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.
|
Displacement of [3H]rauwolscine from Alpha-2 adrenergic receptor of rat cortical membranes
|
Rattus norvegicus
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies.
Year : 1998
Volume : 41
Issue : 21
First Page : 4165
Last Page : 4170
Authors : Tagmatarchis N, Thermos K, Katerinopoulos HE.
Abstract : A series of N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines was synthesized and assayed in vitro for their dopaminergic and alpha-adrenergic activity. Structure-activity relationship (SAR) analysis revealed that the tested benzoquinolines exhibited activity at the D1 rather than the D2 receptor sites in contrast to the D2 receptor subfamily activity reported for their aminotetralin congeners. N-Iodopropenyl substitution was apparently a decisive factor for D1 activity independent of ring substitution pattern. Considering the structural factors influencing alpha-adrenergic activity, in a general trend, N-iodopropenyl analogues were alpha1-active, with the ring-hydroxylated congeners exhibiting the highest affinity. Affinity to the alpha2 receptor was even higher with no detectable trend of SAR. However, a combination of the linear arrangement of the [g]-ring system, combined with the ring hydroxyl and the N-iodopropenyl substitution in compound 5c, resulted in a significant enhancement of alpha2 activity in this series as demonstrated by an IC50 value of 0.5 nM. A new synthetic approach to the [g]benzoquinoline system is also described.
|
The compound was evaluated for the inhibition of [3H]rauwolscine binding to alpha-2-adrenergic receptor from rat cortex
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.
Year : 1986
Volume : 29
Issue : 4
First Page : 463
Last Page : 467
Authors : DeBernardis JF, Kyncl JJ, Basha FZ, Arendsen DL, Martin YC, Winn M, Kerkman DJ.
Abstract : The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).
|
Binding of [3H]prazosin to alpha-1 adrenergic receptor of rat cerebral cortical membranes at 100 uM
|
None
|
18.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses of (R)- and (S)-2- and 6-fluoronorepinephrine and (R)- and (S)-2- and 6-fluoroepinephrine: effect of stereochemistry on fluorine-induced adrenergic selectivities.
Year : 2000
Volume : 43
Issue : 8
First Page : 1611
Last Page : 1619
Authors : Lu SF, Herbert B, Haufe G, Laue KW, Padgett WL, Oshunleti O, Daly JW, Kirk KL.
Abstract : Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroepinephrines (2) were explored. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining steps of two respective routes. Binding studies of the catecholamines with alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined. The assays confirmed that fluorine substitution had marked effects on the affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors, depending on the position of substitution. Thus, a fluoro substituent at the 2-position of (R)-norepinephrine and (R)-epinephrine reduced activity at both alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)-receptors, while fluorination at the 6-position reduced activity at the beta(1)- and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were less predictable.
|
Binding affinity towards Alpha-1A adrenergic receptor in rat submaxillary glands
|
None
|
281.84
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.
Year : 1996
Volume : 39
Issue : 20
First Page : 4116
Last Page : 4119
Authors : Meyer MD, Altenbach RJ, Hancock AA, Buckner SA, Knepper SM, Kerwin JF.
Abstract : The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.
|
Binding affinity for alpha-2 adrenergic receptor in rat cortex using [3H]rauwolscine.
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 5. Resolution, absolute configuration, and pharmacological characterization of the enantiomers of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: a potent agonist at alpha-adrenoceptors.
Year : 1987
Volume : 30
Issue : 6
First Page : 1011
Last Page : 1017
Authors : DeBernardis JF, Kerkman DJ, Arendsen DL, Buckner SA, Kyncl JJ, Hancock AA.
Abstract : (+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.
|
Compound was evaluated for alpha adrenergic binding affinity towards Alpha-2 adrenergic receptor of rat brain
|
None
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
Year : 1992
Volume : 35
Issue : 6
First Page : 1009
Last Page : 1018
Authors : Macchia B, Balsamo A, Breschi MC, Lapucci A, Lucacchini A, Macchia F, Manera C, Martinelli A, Martini C, Martinotti E.
Abstract : The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
|
Binding affinity towards hamster clonal Alpha-1B adrenergic receptor
|
Cricetulus griseus
|
263.03
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.
Year : 1996
Volume : 39
Issue : 20
First Page : 4116
Last Page : 4119
Authors : Meyer MD, Altenbach RJ, Hancock AA, Buckner SA, Knepper SM, Kerwin JF.
Abstract : The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.
|
Binding affinity for alpha-1 adrenergic receptor in rat liver using [3H]prazosin.
|
None
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 5. Resolution, absolute configuration, and pharmacological characterization of the enantiomers of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: a potent agonist at alpha-adrenoceptors.
Year : 1987
Volume : 30
Issue : 6
First Page : 1011
Last Page : 1017
Authors : DeBernardis JF, Kerkman DJ, Arendsen DL, Buckner SA, Kyncl JJ, Hancock AA.
Abstract : (+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.
|
Binding affinity towards Alpha-1 adrenergic receptor of rat brain
|
Rattus norvegicus
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
Year : 1992
Volume : 35
Issue : 6
First Page : 1009
Last Page : 1018
Authors : Macchia B, Balsamo A, Breschi MC, Lapucci A, Lucacchini A, Macchia F, Manera C, Martinelli A, Martini C, Martinotti E.
Abstract : The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
|
Compound was evaluated for inhibition of [3H]prazosin binding to Alpha-1 adrenergic receptor in rat forebrain homogenate.
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : (alpha S)-erythro-alpha-methylepinephrine: preparation and stereoselective binding to adrenergic receptors in rat forebrain.
Year : 1981
Volume : 24
Issue : 10
First Page : 1261
Last Page : 1263
Authors : Taylor CA, Smith HE, Goldberg MR, Robertson D.
Abstract : The enantiomers of a number of catecholamines, including (alpha S)- and (alpha R)-erythro-alpha-methylepinephrine, were evaluated for their capacity to compete for binding sites in rat forebrain homogenates with [3H]prazosin, a ligand which selectively binds to adrenergic receptors of the alpha 1 subtype. (alpha R)-erythro-alpha-Methylepinephrine is devoid of apparent biological activity, but the activity of the alpha S isomer is substantial. The latter is less active than the endogeneous catecholamines, (R)-norepinephrine and (R)-epinephrine, but the stereospecific competition for [3H]prazosin binding sites by the catecholamine isomers with the beta R configuration is additional evidence that (alpha S)-erythro-alpha-methylepinephrine may be a biologically active metabolite of L-alpha-methyl-3,4-dihydroxyphenylalanine.
|
Compound was evaluated for beta adrenergic binding affinity towards Beta-1 adrenergic receptor of rat brain
|
None
|
126.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
Year : 1992
Volume : 35
Issue : 6
First Page : 1009
Last Page : 1018
Authors : Macchia B, Balsamo A, Breschi MC, Lapucci A, Lucacchini A, Macchia F, Manera C, Martinelli A, Martini C, Martinotti E.
Abstract : The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
|
Tested for binding affinity against beta-1 adrenergic receptor in rat brain using [3H]-CGP- 26505 as radioligand
|
None
|
126.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
Year : 1993
Volume : 36
Issue : 21
First Page : 3077
Last Page : 3086
Authors : Macchia B, Balsamo A, Breschi MC, Chiellini G, Lapucci A, Macchia M, Manera C, Martinelli A, Martini C, Scatizzi R.
Abstract : In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
|
Activity for Beta-2 adrenergic receptor was assessed from effect on relaxation of guinea pig trachea.
|
Cavia porcellus
|
213.0
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.
|
Agonistic potency at beta-1 adrenergic receptor for the percent maximal increase in contraction rate of isolated guinea pig atria
|
Cavia porcellus
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic activities of ring-fluorinated epinephrines.
Year : 1988
Volume : 31
Issue : 10
First Page : 1972
Last Page : 1977
Authors : Adejare A, Gusovsky F, Padgett W, Creveling CR, Daly JW, Kirk KL.
Abstract : The study of chemical and biological effects of fluorine substitution on the aromatic ring of catecholamines has now been extended to epinephrine (Epi). 2- and 6-fluoroepinephrines (2-FEpi and 6-FEpi) have been synthesized. Fluorine substitution on the 2- or 6-carbon of the aromatic ring alters the selectivity of epinephrine toward alpha- and beta-adrenergic receptors, similar in manner to the change in selectivity seen with norepinephrine (NE). Thus, 2-FEpi is a relatively selective beta-adrenergic ligand, while 6-FEpi is a relatively selective alpha-adrenergic ligand. Fluorine substitution of Epi also can markedly increase potency at either alpha- or beta-adrenergic receptors.
|
Effective concentration for Beta-1 adrenergic receptor mediated inhibition of neurotransmission in field-stimulated reserpine pretreated guinea pig ileum.
|
Cavia porcellus
|
30.0
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 beta-1 adrenergic receptor in guinea pig cerebral cortical membranes by displacement of Dihydro-[3H]-alprenolol
|
Cavia porcellus
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic activities of ring-fluorinated epinephrines.
Year : 1988
Volume : 31
Issue : 10
First Page : 1972
Last Page : 1977
Authors : Adejare A, Gusovsky F, Padgett W, Creveling CR, Daly JW, Kirk KL.
Abstract : The study of chemical and biological effects of fluorine substitution on the aromatic ring of catecholamines has now been extended to epinephrine (Epi). 2- and 6-fluoroepinephrines (2-FEpi and 6-FEpi) have been synthesized. Fluorine substitution on the 2- or 6-carbon of the aromatic ring alters the selectivity of epinephrine toward alpha- and beta-adrenergic receptors, similar in manner to the change in selectivity seen with norepinephrine (NE). Thus, 2-FEpi is a relatively selective beta-adrenergic ligand, while 6-FEpi is a relatively selective alpha-adrenergic ligand. Fluorine substitution of Epi also can markedly increase potency at either alpha- or beta-adrenergic receptors.
|
Stimulation of cyclic AMP accumulation in C6 glioma cells expressing adrenergic beta receptor
|
Rattus norvegicus
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses of 2,5- and 2,6-difluoronorepinephrine, 2,5-difluoroepinephrine, and 2,6-difluorophenylephrine: effect of disubstitution with fluorine on adrenergic activity.
Year : 1993
Volume : 36
Issue : 24
First Page : 3947
Last Page : 3955
Authors : Chen GT, King M, Gusovsky F, Creveling CR, Daly JW, Chen BH, Nie JY, Kirk KL.
Abstract : Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both alpha- and beta-adrenergic receptors. These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases alpha-adrenergic activity whereas 6-fluoro substitution decreases beta-adrenergic activity.
|
Agonist required to inhibit Dopamine receptor D2 photoinactivation by 50% with Iodazidoclebopride using [3H]-Spiperone
|
Canis lupus familiaris
|
8e-05
nM
|
|
Journal : J. Med. Chem.
Title : Novel photoaffinity label for the dopamine D2 receptor: synthesis of 4-azido-5-iodo-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl] benzamide (iodoazidoclebopride, IAC) and the corresponding 125I-labeled analogue (125IAC).
Year : 1985
Volume : 28
Issue : 4
First Page : 405
Last Page : 407
Authors : Neumeyer JL, Guan JH, Niznik HB, Dumbrille-Ross A, Seeman P, Padmanabhan S, Elmaleh DR.
|
Binding of [3H]clonidine to alpha-2-adrenergic receptor of rat cerebral cortical membranes
|
None
|
30.0
nM
|
|
Binding of [3H]clonidine to alpha-2-adrenergic receptor of rat cerebral cortical membranes
|
None
|
340.0
nM
|
|
Binding of [3H]clonidine to alpha-2-adrenergic receptor of rat cerebral cortical membranes
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses of (R)- and (S)-2- and 6-fluoronorepinephrine and (R)- and (S)-2- and 6-fluoroepinephrine: effect of stereochemistry on fluorine-induced adrenergic selectivities.
Year : 2000
Volume : 43
Issue : 8
First Page : 1611
Last Page : 1619
Authors : Lu SF, Herbert B, Haufe G, Laue KW, Padgett WL, Oshunleti O, Daly JW, Kirk KL.
Abstract : Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroepinephrines (2) were explored. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining steps of two respective routes. Binding studies of the catecholamines with alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined. The assays confirmed that fluorine substitution had marked effects on the affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors, depending on the position of substitution. Thus, a fluoro substituent at the 2-position of (R)-norepinephrine and (R)-epinephrine reduced activity at both alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)-receptors, while fluorination at the 6-position reduced activity at the beta(1)- and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were less predictable.
|
Agonist activity at human adrenergic alpha-2C receptor expressed in CHO cells assessed as extracellular acidification by cytosensor microphysiometry
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2-adrenoreceptors profile modulation. 2. Biphenyline analogues as tools for selective activation of the alpha 2C-subtype.
Year : 2004
Volume : 47
Issue : 25
First Page : 6160
Last Page : 6173
Authors : Gentili F, Ghelfi F, Giannella M, Piergentili A, Pigini M, Quaglia W, Vesprini C, Crassous PA, Paris H, Carrieri A.
Abstract : A series of derivatives structurally related to biphenyline (3) was designed with the aim to modulate selectivity toward the alpha(2)-AR subtypes. The results obtained demonstrated that the presence of a correctly oriented function with positive electronic effect (+sigma) in portion X of the ligands is an important factor for significant alpha(2C)-subtype selectivity (imidazolines 5, 13, 16, and 19). Homology modeling and docking studies support experimental data and highlight the crucial role for the hydrogen bond between the pyridine nitrogen in position 3 of 5 and the NH-indole ring of Trp6.48, which is favorably oriented in the alpha(2C)-subtype, only.
|
Agonist activity at human adrenergic alpha-2B receptor expressed in CHO cells assessed as extracellular acidification by cytosensor microphysiometry
|
Homo sapiens
|
61.66
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2-adrenoreceptors profile modulation. 2. Biphenyline analogues as tools for selective activation of the alpha 2C-subtype.
Year : 2004
Volume : 47
Issue : 25
First Page : 6160
Last Page : 6173
Authors : Gentili F, Ghelfi F, Giannella M, Piergentili A, Pigini M, Quaglia W, Vesprini C, Crassous PA, Paris H, Carrieri A.
Abstract : A series of derivatives structurally related to biphenyline (3) was designed with the aim to modulate selectivity toward the alpha(2)-AR subtypes. The results obtained demonstrated that the presence of a correctly oriented function with positive electronic effect (+sigma) in portion X of the ligands is an important factor for significant alpha(2C)-subtype selectivity (imidazolines 5, 13, 16, and 19). Homology modeling and docking studies support experimental data and highlight the crucial role for the hydrogen bond between the pyridine nitrogen in position 3 of 5 and the NH-indole ring of Trp6.48, which is favorably oriented in the alpha(2C)-subtype, only.
|
Agonist activity at human adrenergic alpha-2A receptor expressed in CHO cells assessed as extracellular acidification by cytosensor microphysiometry
|
Homo sapiens
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2-adrenoreceptors profile modulation. 2. Biphenyline analogues as tools for selective activation of the alpha 2C-subtype.
Year : 2004
Volume : 47
Issue : 25
First Page : 6160
Last Page : 6173
Authors : Gentili F, Ghelfi F, Giannella M, Piergentili A, Pigini M, Quaglia W, Vesprini C, Crassous PA, Paris H, Carrieri A.
Abstract : A series of derivatives structurally related to biphenyline (3) was designed with the aim to modulate selectivity toward the alpha(2)-AR subtypes. The results obtained demonstrated that the presence of a correctly oriented function with positive electronic effect (+sigma) in portion X of the ligands is an important factor for significant alpha(2C)-subtype selectivity (imidazolines 5, 13, 16, and 19). Homology modeling and docking studies support experimental data and highlight the crucial role for the hydrogen bond between the pyridine nitrogen in position 3 of 5 and the NH-indole ring of Trp6.48, which is favorably oriented in the alpha(2C)-subtype, only.
|
Agonistic potency at human adrenergic alpha-2A receptor expressed in CHO cells assessed as forskolin-induced cAMP accumulation
|
Homo sapiens
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist.
Year : 2007
Volume : 50
Issue : 16
First Page : 3964
Last Page : 3968
Authors : Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M.
Abstract : To assess the stereochemical requirements for efficient alpha2C-adrenoreceptor activation, the enantiomeric forms of m-nitrobiphenyline [(+/-)-5] were prepared and tested on cells expressing the human alpha2-adrenoreceptor subtypes. The importance of chirality was confirmed, since the enantiomer (R)-(+)-5 was much more efficient than (S)-(-)-5 in producing alpha2C-activation. Surprising reversal of enantioselectivity was observed with respect to structurally similar biphenyline [(+/-)-1] whose (S)-(-)-form proved the preferred alpha2C-configuration.
|
Agonistic potency at human adrenergic alpha-2B receptor expressed in CHO cells assessed as forskolin-induced cAMP accumulation
|
Homo sapiens
|
61.66
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist.
Year : 2007
Volume : 50
Issue : 16
First Page : 3964
Last Page : 3968
Authors : Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M.
Abstract : To assess the stereochemical requirements for efficient alpha2C-adrenoreceptor activation, the enantiomeric forms of m-nitrobiphenyline [(+/-)-5] were prepared and tested on cells expressing the human alpha2-adrenoreceptor subtypes. The importance of chirality was confirmed, since the enantiomer (R)-(+)-5 was much more efficient than (S)-(-)-5 in producing alpha2C-activation. Surprising reversal of enantioselectivity was observed with respect to structurally similar biphenyline [(+/-)-1] whose (S)-(-)-form proved the preferred alpha2C-configuration.
|
Agonistic potency at human adrenergic Alpha-2C receptor expressed in CHO cells assessed as forskolin-induced cAMP accumulation
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist.
Year : 2007
Volume : 50
Issue : 16
First Page : 3964
Last Page : 3968
Authors : Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M.
Abstract : To assess the stereochemical requirements for efficient alpha2C-adrenoreceptor activation, the enantiomeric forms of m-nitrobiphenyline [(+/-)-5] were prepared and tested on cells expressing the human alpha2-adrenoreceptor subtypes. The importance of chirality was confirmed, since the enantiomer (R)-(+)-5 was much more efficient than (S)-(-)-5 in producing alpha2C-activation. Surprising reversal of enantioselectivity was observed with respect to structurally similar biphenyline [(+/-)-1] whose (S)-(-)-form proved the preferred alpha2C-configuration.
|
Agonist activity at human adrenergic beta-3 receptor expressed in CHO cells assessed as cAMP levels by DELFIA method
|
Homo sapiens
|
5.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.
Year : 2008
Volume : 16
Issue : 5
First Page : 2473
Last Page : 2488
Authors : Perrone MG, Santandrea E, Bleve L, Vitale P, Colabufo NA, Jockers R, Milazzo FM, Sciarroni AF, Scilimati A.
Abstract : Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
|
Agonist activity at human adrenergic beta3 receptor expressed in CHO cells assessed as [3H]cAMP levels by radiolabeled ligand based assay
|
Homo sapiens
|
6.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.
Year : 2008
Volume : 16
Issue : 5
First Page : 2473
Last Page : 2488
Authors : Perrone MG, Santandrea E, Bleve L, Vitale P, Colabufo NA, Jockers R, Milazzo FM, Sciarroni AF, Scilimati A.
Abstract : Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
|
Agonist activity at human recombinant adrenergic alpha2A receptor expressed in CHO cells assessed as stimulation of extracellular acidification
|
Homo sapiens
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.
Year : 2008
Volume : 51
Issue : 14
First Page : 4289
Last Page : 4299
Authors : Gentili F, Cardinaletti C, Vesprini C, Carrieri A, Ghelfi F, Farande A, Giannella M, Piergentili A, Quaglia W, Laurila JM, Huhtinen A, Scheinin M, Pigini M.
Abstract : The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.
|
Agonist activity at human recombinant adrenergic alpha2B receptor expressed in CHO cells
|
Homo sapiens
|
61.66
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.
Year : 2008
Volume : 51
Issue : 14
First Page : 4289
Last Page : 4299
Authors : Gentili F, Cardinaletti C, Vesprini C, Carrieri A, Ghelfi F, Farande A, Giannella M, Piergentili A, Quaglia W, Laurila JM, Huhtinen A, Scheinin M, Pigini M.
Abstract : The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.
|
Agonist activity at human recombinant adrenergic Alpha-2C receptor expressed in CHO cells assessed as stimulation of extracellular acidification
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.
Year : 2008
Volume : 51
Issue : 14
First Page : 4289
Last Page : 4299
Authors : Gentili F, Cardinaletti C, Vesprini C, Carrieri A, Ghelfi F, Farande A, Giannella M, Piergentili A, Quaglia W, Laurila JM, Huhtinen A, Scheinin M, Pigini M.
Abstract : The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.
|
Agonist activity at human Alpha-2C adrenoceptor expressed in CHO cells assessed as extracellular acidification by cytosensor microphysiometry
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Might adrenergic alpha2C-agonists/alpha2A-antagonists become novel therapeutic tools for pain treatment with morphine?
Year : 2009
Volume : 52
Issue : 22
First Page : 7319
Last Page : 7322
Authors : Cardinaletti C, Mattioli L, Ghelfi F, Del Bello F, Giannella M, Bruzzone A, Paris H, Perfumi M, Piergentili A, Quaglia W, Pigini M.
Abstract : The imidazoline nucleus linked in position 2 via an oxyethylene bridge to a phenyl ring carrying an ortho substituent of moderate steric bulk provided alpha(2)-adrenergic (AR) ligands endowed with significant alpha(2C)-agonism/alpha(2A)-antagonism. Similar behavior was displayed by cirazoline (12). For their positive morphine analgesia modulation (due to alpha(2C)-AR stimulation) and sedation overcoming (due to alpha(2A)-AR antagonism), 8 and 11 might be useful as adjuvant agents in the management of pain with morphine.
|
Agonist activity at human alpha2A adrenoceptor expressed in CHO cells assessed as extracellular acidification by cytosensor microphysiometry
|
Homo sapiens
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : Might adrenergic alpha2C-agonists/alpha2A-antagonists become novel therapeutic tools for pain treatment with morphine?
Year : 2009
Volume : 52
Issue : 22
First Page : 7319
Last Page : 7322
Authors : Cardinaletti C, Mattioli L, Ghelfi F, Del Bello F, Giannella M, Bruzzone A, Paris H, Perfumi M, Piergentili A, Quaglia W, Pigini M.
Abstract : The imidazoline nucleus linked in position 2 via an oxyethylene bridge to a phenyl ring carrying an ortho substituent of moderate steric bulk provided alpha(2)-adrenergic (AR) ligands endowed with significant alpha(2C)-agonism/alpha(2A)-antagonism. Similar behavior was displayed by cirazoline (12). For their positive morphine analgesia modulation (due to alpha(2C)-AR stimulation) and sedation overcoming (due to alpha(2A)-AR antagonism), 8 and 11 might be useful as adjuvant agents in the management of pain with morphine.
|
Inhibition of adipogenesis in mouse 3T3L1 cells assessed as triglyceride accumulation after 7 days
|
Mus musculus
|
69.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Hydroxylated sclerosporin derivatives from the marine-derived fungus Cadophora malorum.
Year : 2010
Volume : 73
Issue : 3
First Page : 476
Last Page : 478
Authors : Almeida C, Eguereva E, Kehraus S, Siering C, König GM.
Abstract : The marine-derived fungus Cadophora malorum was isolated from the green alga Enteromorpha sp. Growth on a biomalt medium supplemented with sea salt yielded an extract, from which we have isolated sclerosporin and four new hydroxylated sclerosporin derivatives, namely, 15-hydroxysclerosporin (2), 12-hydroxysclerosporin (3), 11-hydroxysclerosporin (4), and 8-hydroxysclerosporin (5). The compounds were evaluated in various biological activity assays. Compound 5 showed a weak fat-accumulation inhibitory activity against 3T3-L1 murine adipocytes.
|
Cytotoxicity against mouse 3T3L1 cells assessed as cell viability after 7 days
|
Mus musculus
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Hydroxylated sclerosporin derivatives from the marine-derived fungus Cadophora malorum.
Year : 2010
Volume : 73
Issue : 3
First Page : 476
Last Page : 478
Authors : Almeida C, Eguereva E, Kehraus S, Siering C, König GM.
Abstract : The marine-derived fungus Cadophora malorum was isolated from the green alga Enteromorpha sp. Growth on a biomalt medium supplemented with sea salt yielded an extract, from which we have isolated sclerosporin and four new hydroxylated sclerosporin derivatives, namely, 15-hydroxysclerosporin (2), 12-hydroxysclerosporin (3), 11-hydroxysclerosporin (4), and 8-hydroxysclerosporin (5). The compounds were evaluated in various biological activity assays. Compound 5 showed a weak fat-accumulation inhibitory activity against 3T3-L1 murine adipocytes.
|
Agonist activity at human recombinant alpha2A adrenergic receptor expressed in CHO cells assessed as induction of [35S]GTPgammaS binding after 60 mins by scintillation counting
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor.
Year : 2011
Volume : 19
Issue : 1
First Page : 321
Last Page : 329
Authors : Sączewski F, Kornicka A, Hudson AL, Laird S, Scheinin M, Laurila JM, Rybczyńska A, Boblewski K, Lehmann A, Gdaniec M.
Abstract : A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective α(2)-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display α(2)-adrenoceptor affinity at nanomolar concentrations (K(i)=39.4, 15.9 and 22.6nM, respectively) and relatively high α(2)/I(1) selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at α(2A)-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01mg/kg iv.
|
Agonist activity at human adrenoceptor alpha2A expressed in CHOK1 cells assessed as stimulation of agonist-induced [35S]GTPgammaS binding by scintillation counting
|
Homo sapiens
|
118.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological activities of 2-[(heteroaryl)methyl]imidazolines.
Year : 2012
Volume : 20
Issue : 1
First Page : 108
Last Page : 116
Authors : Saczewski J, Hudson A, Scheinin M, Rybczynska A, Ma D, Saczewski F, Laird S, Laurila JM, Boblewski K, Lehmann A, Gu J, Watts H.
Abstract : A series of 2-[(heteroaryl)methyl]imidazolines was synthesized and tested for their activities at α(1)- and α(2)-adrenoceptors and imidazoline I(1) and I(2) receptors. The most active 2-[(indazol-1-yl)methyl]imidazolines showed high or moderate affinities for α(1)- and α(2)-adrenoceptors. However, their intrinsic activities at α(2A)-adrenoceptors proved to be negligible. A selected 7-chloro derivative behaved as a potent α(1)-adrenoceptor antagonist and exhibited peripherally mediated hypotensive effects in rats.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
112.9
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
102.31
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Agonist activity at human alpha2A adrenoceptor expressed in CHO-K1 cells after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
128.82
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Fluorinated analogues of marsanidine, a highly α2-AR/imidazoline I1 binding site-selective hypotensive agent. Synthesis and biological activities.
Year : 2014
Volume : 87
First Page : 386
Last Page : 397
Authors : Wasilewska A, Sączewski F, Hudson AL, Ferdousi M, Scheinin M, Laurila JM, Rybczyńska A, Boblewski K, Lehmann A.
Abstract : The aim of these studies was to establish the influence of fluorination of the indazole ring on the pharmacological properties of two selective α2-adrenoceptor (α2-AR) agonists: 1-[(imidazolidin-2-yl)imino]-1H-indazole (marsanidine, A) and its methylene analogue 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (B). Introduction of fluorine into the indazole ring of A and B reduced both binding affinity and α2-AR/I1 imidazoline binding site selectivity. The most α2-AR-selective ligands were 6-fluoro-1-[(imidazolidin-2-yl)imino]-1H-indazole (6c) and 7-fluoro-1-[(imidazolidin-2-yl)imino]-1H-indazole (6d). The in vivo cardiovascular properties of fluorinated derivatives of A and B revealed that in both cases the C-7 fluorination leads to compounds with the highest hypotensive and bradycardic activities. The α2-AR partial agonist 6c was prepared as a potential lead compound for development of a radiotracer for PET imaging of brain α2-ARs.
|
Agonist activity at human alpha1A-adrenergic receptor expressed in HEK293 cells assessed as calcium flux by fluorescence assay
|
Homo sapiens
|
9.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects.
Year : 2015
Volume : 58
Issue : 15
First Page : 6048
Last Page : 6057
Authors : Wada Y, Shirahashi H, Iwanami T, Ogawa M, Nakano S, Morimoto A, Kasahara K, Tanaka E, Takada Y, Ohashi S, Mori M, Shuto S.
Abstract : Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β3-AR agonistic activity versus α1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent β3-AR agonistic activity (EC50 = 13 nM) and high selectivity (α1A/β3 = >769-fold). Compound 11 was also inactive toward β1 and β2-ARs and showed dose dependent β3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.
|
Agonist activity at human recombinant Alpha-2 adrenergic receptor expressed in CHOK1 cells after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
166.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Transfer of SAR information from hypotensive indazole to indole derivatives acting at α-adrenergic receptors: In vitro and in vivo studies.
Year : 2016
Volume : 115
First Page : 406
Last Page : 415
Authors : Sączewski J, Hudson A, Scheinin M, Wasilewska A, Sączewski F, Rybczyńska A, Ferdousi M, Laurila JM, Boblewski K, Lehmann A, Watts H, Ma D.
Abstract : In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described α1-adrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the α-adrenergic properties of the indazole core were transferable to the indole core. The newly obtained 1-[(imidazolin-2-yl)methyl]indole analogues were screened in vitro for their binding affinities for α1-and α2-adrenoceptors, which allowed the identification of the target-based SAR transfer (T_SAR transfer) as well as structure-based SAR transfer (S_SAR transfer) events. However, when screened in vivo with use of anaesthetized male Wistar rats, the new indole ligands showed a different hemodynamic profile than expected. Instead of the immediate hypotensive effect characteristic of peripheral vasodilatator α1 blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [(35)S]GTPγS binding assay, where the indole analogues displayed partial agonist properties at α2-adrenergic receptors. Since no correlation was found between the in vitro binding to α-adrenoceptors and the in vivo hemodynamic effects of the two series of indazole and indole bioisosteric compounds, in a search for new imidazoline-containing adrenergic drugs, the structure-based SAR transfer information obtained from in vitro binding studies should be treated with caution.
|
Binding affinity to mouse alpha-2C receptor expressed in COS7 cells
|
Mus musculus
|
650.0
nM
|
|
Title : Novel methods for identifying improved, non-sedating alpha-2 agonists
Year : 2005
|
Agonist activity at recombinant human alpha1A adrenergic receptor expressed in HEK293 cells assessed as intercellular Ca mobilization by Fura-2AM dye-based fluorescence assay
|
Homo sapiens
|
9.1
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.
Year : 2017
Volume : 60
Issue : 8
First Page : 3252
Last Page : 3265
Authors : Wada Y, Nakano S, Morimoto A, Kasahara KI, Hayashi T, Takada Y, Suzuki H, Niwa-Sakai M, Ohashi S, Mori M, Hirokawa T, Shuto S.
Abstract : We previously discovered that indazole derivative 8 was a highly selective β3-adrenergic receptor (β3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β3-AR agonist (EC50 = 18 nM) being inactive to β1-, β2-, and α1A-AR (β1/β3, β2/β3, and α1A/β3 > 556-fold). Compound 15 showed dose-dependent β3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-31.86
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-11.01
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.21
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.21
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
