|
Inhibition of [3H]5-HT radioligand binding against 5-hydroxytryptamine 1 receptor
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
Year : 1989
Volume : 32
Issue : 5
First Page : 1052
Last Page : 1056
Authors : Martin GE, Elgin RJ, Mathiasen JR, Davis CB, Kesslick JM, Baldy WJ, Shank RP, DiStefano DL, Fedde CL, Scott MK.
Abstract : Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
|
Binding affinity towards rat 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT radioligand.
|
None
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1, 3-dioxoperhydroimidazo[1,5-alpha]pyridine: a selective 5-HT1A receptor agonist.
Year : 1996
Volume : 39
Issue : 22
First Page : 4439
Last Page : 4450
Authors : López-Rodríguez ML, Rosado ML, Benhamú B, Morcillo MJ, Sanz AM, Orensanz L, Beneitez ME, Fuentes JA, Manzanares J.
Abstract : A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.
|
In vitro ability to displace [3H]8-hydroxy-2-(di-n-propylamino) tetralin binding from 5-hydroxytryptamine 1A receptor site in rat brain hippocampus
|
None
|
143.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies of central nervous system agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A receptor site.
Year : 1992
Volume : 35
Issue : 13
First Page : 2369
Last Page : 2374
Authors : Mokrosz JL, Pietrasiewicz M, Duszyńska B, Cegła MT.
Abstract : The effect of the hydrocarbon chain of the model 4-substituted 1-(3-chlorophenyl)piperazines 12-31 on their affinity for 5-HT1A receptor sites was investigated. It was found that elongation of the 4-n-alkyl chain strongly increases the 5-HT1A affinity of the investigated compounds. The affinity reaches the maximum (Ki = 2.67 nM) for the n-hexyl derivative 20. It was shown that hydrophobic interactions of N-4 substituents of 1-arylpiperazines significantly contribute to their 5-HT1A affinity. The specific binding constant was defined as the receptor affinity of the protonated species of compounds under physiological conditions. The range of Ki(AH+) = 1 - 3 x 10(-11) M is a specific affinity limit of the investigated class of compounds at the 5-HT1A receptor sites.
|
Displacement of radioligand [3H]2-(di-N-propylamino)-8-hydroxytetralin from 5-hydroxytryptamine 1A receptor in rat frontal cortex homogenate (experiment 1)
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents.
Year : 1993
Volume : 36
Issue : 19
First Page : 2751
Last Page : 2760
Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.
Abstract : Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.
|
Displacement of radioligand [3H]2-(di-N-propylamino)-8-hydroxytetralin from 5-hydroxytryptamine 1A receptor in rat frontal cortex homogenate (experiment 2)
|
None
|
143.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents.
Year : 1993
Volume : 36
Issue : 19
First Page : 2751
Last Page : 2760
Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.
Abstract : Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.
|
Evaluated for binding affinity towards 5-hydroxytryptamine 1A receptor in rat brain
|
None
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Arylpiperazine derivatives as high-affinity 5-HT1A serotonin ligands.
Year : 1988
Volume : 31
Issue : 10
First Page : 1968
Last Page : 1971
Authors : Glennon RA, Naiman NA, Lyon RA, Titeler M.
Abstract : Although simple arylpiperazines are commonly considered to be moderately selective for 5-HT1B serotonin binding sites, N4-substitution of such compounds can enhance their affinity for 5-HT1A sites and/or decrease their affinity for 5-HT1B sites. A small series of 4-substituted 1-arylpiperazines was prepared in an attempt to develop agents with high affinity for 5-HT1A sites. Derivatives where the aryl portion is phenyl, 2-methoxyphenyl, or 1-naphthyl, and the 4-substituent is either a phthalimido or benzamido group at a distance of four methylene units away from the piperazine 4-position, display high affinity for these sites. One of these compounds, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (18), possesses a higher affinity than 5-HT and represents the highest affinity (Ki = 0.6 nM) agent yet reported for 5-HT1A sites.
|
Binding affinity at rat 5-hydroxytryptamine 1A receptor by [3H]WB-4101 displacement.
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
Year : 1989
Volume : 32
Issue : 5
First Page : 1052
Last Page : 1056
Authors : Martin GE, Elgin RJ, Mathiasen JR, Davis CB, Kesslick JM, Baldy WJ, Shank RP, DiStefano DL, Fedde CL, Scott MK.
Abstract : Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
|
Binding affinity of a compound to rat brain 5-hydroxytryptamine 1A (serotonin) receptor assayed by radiolabeled [3H]-8-OH-DPAT ligand displacement
|
None
|
144.54
nM
|
|
Journal : J. Med. Chem.
Title : Binding of arylpiperazines, (aryloxy)propanolamines, and tetrahydropyridylindoles to the 5-HT1A receptor: contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-affinity relationship models.
Year : 1996
Volume : 39
Issue : 1
First Page : 126
Last Page : 134
Authors : Gaillard P, Carrupt PA, Testa B, Schambel P.
Abstract : A set of 280 5-HT1A receptor ligands were selected from available literature data according to predefined criteria and subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis. No model was obtained for serotonin analogues (19 compounds) and aminotetralins (60 compounds), despite a variety of alignment hypotheses being tried. In contrast, the steric, electrostatic, and lipophilicity fields alone and in combination yielded informative models for arylpiperazines (101 training compounds and 12 test compounds), (aryloxy)propanolamines (30 training compounds and four test compounds), and tetrahydropyridylindoles (54 training compounds) taken separately (models A, B, and C). Arylpiperazines and (aryloxy)propanolamines were then combined successfully to yield reasonably good models for 131 compounds (model D). In a last step, the three chemical classes (185 compounds) were combined, again successfully (model E). This stepwise procedure not only ascertains self-consistency in alignments but it also allows statistical signals (i.e., favorable or unfavorable regions around molecules) to emerge which cannot exist in a single chemical class. The models so obtained reveal a number of interaction sites between ligands and the 5-HT1A receptor, and extend the information gathered from a model based on homology modeling.
|
Binding affinity at rat 5-hydroxytryptamine 1B receptor by [3H]5-HT displacement.
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
Year : 1989
Volume : 32
Issue : 5
First Page : 1052
Last Page : 1056
Authors : Martin GE, Elgin RJ, Mathiasen JR, Davis CB, Kesslick JM, Baldy WJ, Shank RP, DiStefano DL, Fedde CL, Scott MK.
Abstract : Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
|
Binding affinity (Ki) to rat cortical membranes at 5-HT1B binding site by using [125 I] ICYP as a radioligand.
|
None
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : Central serotonin receptors as targets for drug research.
Year : 1987
Volume : 30
Issue : 1
First Page : 1
Last Page : 12
Authors : Glennon RA.
|
Functional activity against human 5-hydroxytryptamine 2A receptor expressed in CHO cells using fluorometric imaging plate reader
|
Homo sapiens
|
75.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indoline derivatives as 5-HT(2C) receptor agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2367
Last Page : 2370
Authors : Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA.
Abstract : A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
|
Affinity for human 5-hydroxytryptamine 2A receptor expressed in mammalian cell line
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indoline derivatives as 5-HT(2C) receptor agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2367
Last Page : 2370
Authors : Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA.
Abstract : A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
|
Binding affinity at rat 5-hydroxytryptamine 2 receptor by [3H]ketanserin displacement.
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
Year : 1989
Volume : 32
Issue : 5
First Page : 1052
Last Page : 1056
Authors : Martin GE, Elgin RJ, Mathiasen JR, Davis CB, Kesslick JM, Baldy WJ, Shank RP, DiStefano DL, Fedde CL, Scott MK.
Abstract : Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
|
Affinity for human 5-hydroxytryptamine 2B receptor expressed in mammalian cell line
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indoline derivatives as 5-HT(2C) receptor agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2367
Last Page : 2370
Authors : Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA.
Abstract : A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
|
Functional activity against human 5-hydroxytryptamine 2C receptor expressed in CHO cells using fluorometric imaging plate reader
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indoline derivatives as 5-HT(2C) receptor agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2367
Last Page : 2370
Authors : Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA.
Abstract : A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
|
Affinity for human 5-hydroxytryptamine 2C receptor expressed in mammalian cell line
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indoline derivatives as 5-HT(2C) receptor agonists.
Year : 2004
Volume : 14
Issue : 9
First Page : 2367
Last Page : 2370
Authors : Bentley JM, Adams DR, Bebbington D, Benwell KR, Bickerdike MJ, Davidson JE, Dawson CE, Dourish CT, Duncton MA, Gaur S, George AR, Giles PR, Hamlyn RJ, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Monck NJ, Pratt RM, Quirk K, Roffey JR, Vickers SP, Cliffe IA.
Abstract : A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
|
Compound was tested for the inhibition of [3H]GR-65630 binding to 5-hydroxytryptamine 3 receptor expressed in NG 108-15 cells
|
None
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for the binding of arylpiperazines and arylbiguanides at 5-HT3 serotonin receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4017
Last Page : 4026
Authors : Dukat M, Abdel-Rahman AA, Ismaiel AM, Ingher S, Teitler M, Gyermek L, Glennon RA.
Abstract : Arylpiperazines are nonselective agents that bind at 5-HT3 serotonin receptors with moderate to high affinity, whereas 1-phenylbiguanide is a low-affinity but more selective 5-HT3 agonist. In an attempt to enhance the affinity of the latter agent, and working with the assumption that similarities might exist between the binding of the two types of agents, we formulated structure-activity relationships for the binding of the arylpiperazines and then incorporated those substituents, leading to high affinity for the arylpiperazines, into 1-phenylbiguanide. A subsequent investigation examined the structure-activity relationships of the arylbiguanides and identified arylguanidines as a novel class of 5-HT3 ligands. Although curious similarities exist between the structure-activity relationships of the arylpiperazines, arylbiguanides, and arylguanidines, it cannot be concluded that all three series of compounds are binding in the same manner. Furthermore, upon investigating pairs of compounds in the three series, the arylpiperazines behaved as 5-HT3 antagonists (von Bezold-Jarisch assay) whereas the arylbiguanides and arylguanidines acted as 5-HT3 agonists.
|
Binding affinity of compound towards rodent 5-hydroxytryptamine 7 receptor
|
None
|
304.0
nM
|
|
Journal : J. Med. Chem.
Title : Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
Year : 2003
Volume : 46
Issue : 14
First Page : 2795
Last Page : 2812
Authors : Glennon RA.
|
Local inhibition constant was determined
|
None
|
131.0
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents.
Year : 1993
Volume : 36
Issue : 19
First Page : 2751
Last Page : 2760
Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.
Abstract : Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.
|
Binding affinity against rat Alpha-1 adrenergic receptor.
|
None
|
236.0
nM
|
|
Journal : J. Med. Chem.
Title : Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
Year : 1989
Volume : 32
Issue : 5
First Page : 1052
Last Page : 1056
Authors : Martin GE, Elgin RJ, Mathiasen JR, Davis CB, Kesslick JM, Baldy WJ, Shank RP, DiStefano DL, Fedde CL, Scott MK.
Abstract : Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
|
Binding to human 5HT2A receptor expressed in CHO cells
|
Homo sapiens
|
75.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.
Year : 2006
Volume : 16
Issue : 3
First Page : 677
Last Page : 680
Authors : Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP.
Abstract : A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
|
Binding to human 5HT2C receptor expressed in CHO cells
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.
Year : 2006
Volume : 16
Issue : 3
First Page : 677
Last Page : 680
Authors : Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP.
Abstract : A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
|
Displacement of [125I]DOI from human 5HT2A
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.
Year : 2006
Volume : 16
Issue : 3
First Page : 677
Last Page : 680
Authors : Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP.
Abstract : A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
|
Displacement of [3H]5-HT from human 5HT2B
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.
Year : 2006
Volume : 16
Issue : 3
First Page : 677
Last Page : 680
Authors : Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP.
Abstract : A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
|
Displacement of [3H]5-HT from human 5HT2C
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.
Year : 2006
Volume : 16
Issue : 3
First Page : 677
Last Page : 680
Authors : Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP.
Abstract : A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
|
Displacement of [125I]DOI from human recombinant 5HT2A expressed in HEK293E cells
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Displacement of [3H]LSD from human recombinant 5HT2B expressed in HEK293E cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Displacement of [125I]DOI from human recombinant 5HT2C expressed in HEK293E cells
|
Homo sapiens
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Activity at human 5HT2A expressed in HEK293E cells assessed as elevation of intracellular calcium by 384-FLIPR assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Activity at human 5HT2B expressed in HEK293E cells assessed as elevation of intracellular calcium by 384-FLIPR assay
|
Homo sapiens
|
287.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Activity at human 5HT2C expressed in HEK293E cells assessed as elevation of intracellular calcium by 384-FLIPR assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Year : 2007
Volume : 50
Issue : 6
First Page : 1365
Last Page : 1379
Authors : Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA.
Abstract : Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
|
Agonist activity at human 5HT2A receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
63.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Agonist activity at human 5HT2C receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Agonist activity at human 5HT2B receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Binding affinity to 5HT1A receptor
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Physical binding pocket induction for affinity prediction.
Year : 2009
Volume : 52
Issue : 19
First Page : 6107
Last Page : 6125
Authors : Langham JJ, Cleves AE, Spitzer R, Kirshner D, Jain AN.
Abstract : Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have limited utility when structural variation moves beyond congeneric series. We present a novel approach based on the multiple-instance learning method of Compass, where a physical model of a binding site is induced from ligands and their corresponding activity data. The model consists of molecular fragments that can account for multiple positions of literal protein residues. We demonstrate the method on 5HT1a ligands by training on a series with limited scaffold variation and testing on numerous ligands with variant scaffolds. Predictive error was between 0.5 and 1.0 log units (0.7-1.4 kcal/mol), with statistically significant rank correlations. Accurate activity predictions of novel ligands were demonstrated using a validation approach where a small number of ligands of limited structural variation known at a fixed time point were used to make predictions on a blind test set of widely varying molecules, some discovered at a much later time point.
|
Agonist activity at human recombinant 5HT2C receptor expressed in CHOK1 cells assessed as induction of calcium mobilization by FLIPR assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of pyridazinone-based 5-HT(2C) agonists.
Year : 2009
Volume : 19
Issue : 19
First Page : 5791
Last Page : 5795
Authors : Allerton CM, Andrews MD, Blagg J, Ellis D, Evrard E, Green MP, Liu KK, McMurray G, Ralph M, Sanderson V, Ward R, Watson L.
Abstract : The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
|
Agonist activity at human recombinant 5HT2A receptor expressed in Swiss mouse 3T3 cells assessed as induction of calcium mobilization by FLIPR assay
|
Homo sapiens
|
167.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of pyridazinone-based 5-HT(2C) agonists.
Year : 2009
Volume : 19
Issue : 19
First Page : 5791
Last Page : 5795
Authors : Allerton CM, Andrews MD, Blagg J, Ellis D, Evrard E, Green MP, Liu KK, McMurray G, Ralph M, Sanderson V, Ward R, Watson L.
Abstract : The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
|
Agonist activity at human recombinant 5HT2B receptor expressed in Swiss mouse 3T3 cells assessed as induction of calcium mobilization by FLIPR assay
|
Homo sapiens
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of pyridazinone-based 5-HT(2C) agonists.
Year : 2009
Volume : 19
Issue : 19
First Page : 5791
Last Page : 5795
Authors : Allerton CM, Andrews MD, Blagg J, Ellis D, Evrard E, Green MP, Liu KK, McMurray G, Ralph M, Sanderson V, Ward R, Watson L.
Abstract : The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
|
Agonist activity at human recombinant 5HT2C receptor expressed in CHO K1 cells assessed as induction of calcium mobilization by FLIPR assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence.
Year : 2009
Volume : 19
Issue : 17
First Page : 4999
Last Page : 5003
Authors : Brennan PE, Whitlock GA, Ho DK, Conlon K, McMurray G.
Abstract : A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
|
Agonist activity at human recombinant 5HT2B receptor assessed as induction of calcium mobilization by FLIPR assay
|
Homo sapiens
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence.
Year : 2009
Volume : 19
Issue : 17
First Page : 4999
Last Page : 5003
Authors : Brennan PE, Whitlock GA, Ho DK, Conlon K, McMurray G.
Abstract : A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
|
Displacement of [125I]DOI from human recombinant 5HT2C receptor expressed in HEK293E cells
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Agonist activity at human recombinant 5HT2C receptor expressed in HEK293E cells by FLIPR assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Displacement of [125I]LSD from human recombinant 5HT2B receptor expressed in HEK293E cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Agonist activity at human recombinant 5HT2B receptor expressed in HEK293E cells by FLIPR assay
|
Homo sapiens
|
287.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Displacement of [125I]DOI from human recombinant 5HT2A receptor expressed in HEK293E cells
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Agonist activity at human recombinant 5HT2A receptor expressed in HEK293E cells by FLIPR assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.
Year : 2010
Volume : 20
Issue : 3
First Page : 1128
Last Page : 1133
Authors : Ahmad S, Ngu K, Miller KJ, Wu G, Hung CP, Malmstrom S, Zhang G, O'Tanyi E, Keim WJ, Cullen MJ, Rohrbach KW, Thomas M, Ung T, Qu Q, Gan J, Narayanan R, Pelleymounter MA, Robl JA.
Abstract : Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
|
Displacement of [3H]LSD from rat kidney proximal convoluted tubule 5HT7R expressed in COS7 cells
|
Rattus norvegicus
|
352.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin(7) (5-HT(7)) receptor with agonist or antagonist action in vitro or ex vivo.
Year : 2012
Volume : 55
Issue : 14
First Page : 6375
Last Page : 6380
Authors : Lacivita E, Patarnello D, Stroth N, Caroli A, Niso M, Contino M, De Giorgio P, Di Pilato P, Colabufo NA, Berardi F, Perrone R, Svenningsson P, Hedlund PB, Leopoldo M.
Abstract : Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic α(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells.
|
Antiobesity activity in C57BL/6 mouse assessed as inhibition of food intake at 5.6 mg/kg, ip measured after 2 to 12 hrs relative to vehicle-treated control
|
Mus musculus
|
13.12
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.
Year : 2013
Volume : 63
First Page : 558
Last Page : 569
Authors : Yang HY, Tae J, Seo YW, Kim YJ, Im HY, Choi GD, Cho H, Park WK, Kwon OS, Cho YS, Ko M, Jang H, Lee J, Choi K, Kim CH, Lee J, Pae AN.
Abstract : Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.
|
Agonist activity at serotonin-activated human recombinant 5HT-2A receptor expressed in HEK293 cells assessed as increase in intracellular calcium level after 5 mins measured for 1 min by fluorescence assay
|
Homo sapiens
|
7.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.
Year : 2013
Volume : 63
First Page : 558
Last Page : 569
Authors : Yang HY, Tae J, Seo YW, Kim YJ, Im HY, Choi GD, Cho H, Park WK, Kwon OS, Cho YS, Ko M, Jang H, Lee J, Choi K, Kim CH, Lee J, Pae AN.
Abstract : Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.
|
Agonist activity at serotonin-activated human recombinant 5HT-2C receptor expressed in HEK293 cells assessed as increase in intracellular calcium level after 5 mins measured for 1 min by fluorescence assay
|
Homo sapiens
|
8.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.
Year : 2013
Volume : 63
First Page : 558
Last Page : 569
Authors : Yang HY, Tae J, Seo YW, Kim YJ, Im HY, Choi GD, Cho H, Park WK, Kwon OS, Cho YS, Ko M, Jang H, Lee J, Choi K, Kim CH, Lee J, Pae AN.
Abstract : Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.
|
Binding affinity to SERT (unknown origin)
|
Homo sapiens
|
271.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.
Year : 2016
Volume : 26
Issue : 3
First Page : 914
Last Page : 920
Authors : Éliás O, Nógrádi K, Domány G, Szakács Z, Kóti J, Szántay C, Tarcsay Á, Keserű GM, Gere A, Kiss B, Kurkó D, Kolok S, Némethy Z, Kapui Z, Hellinger É, Vastag M, Sághy K, Kedves R, Gyertyán I.
Abstract : As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
|
Binding affinity to 5HT2C (unknown origin)
|
Homo sapiens
|
27.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.
Year : 2016
Volume : 26
Issue : 3
First Page : 914
Last Page : 920
Authors : Éliás O, Nógrádi K, Domány G, Szakács Z, Kóti J, Szántay C, Tarcsay Á, Keserű GM, Gere A, Kiss B, Kurkó D, Kolok S, Némethy Z, Kapui Z, Hellinger É, Vastag M, Sághy K, Kedves R, Gyertyán I.
Abstract : As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
|
Binding affinity to 5HT2A (unknown origin)
|
Homo sapiens
|
273.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.
Year : 2016
Volume : 26
Issue : 3
First Page : 914
Last Page : 920
Authors : Éliás O, Nógrádi K, Domány G, Szakács Z, Kóti J, Szántay C, Tarcsay Á, Keserű GM, Gere A, Kiss B, Kurkó D, Kolok S, Némethy Z, Kapui Z, Hellinger É, Vastag M, Sághy K, Kedves R, Gyertyán I.
Abstract : As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
|
Agonist activity at unedited 5-HT2C receptor (unknown origin) expressed in HEK293 cells assessed as [3H]inositol phosphate accumulation after 2 hrs by scintillation counting
|
Homo sapiens
|
12.59
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Agonist activity at 5-HT2B receptor (unknown origin) expressed in HEK293 cells assessed as [3H]inositol phosphate accumulation after 2 hrs by scintillation counting
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Displacement of [125I]DOI from recombinant human 5-HT2C receptor expressed in HEK293 cell membranes after 1 hr by scintillation counting
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Displacement of [125I]DOI from recombinant human 5-HT2B receptor expressed in HEK293 cell membranes after 1 hr by scintillation counting
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Agonist activity at 5-HT2A receptor (unknown origin) expressed in HEK293 cells assessed as [3H]inositol phosphate accumulation after 2 hrs by scintillation counting
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Displacement of [125I]DOI from recombinant human 5-HT2A receptor expressed in HEK293 cell membranes after 1 hr by scintillation counting
|
Homo sapiens
|
25.12
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor.
Year : 2016
Volume : 26
Issue : 24
First Page : 5877
Last Page : 5882
Authors : Schrader TO, Kasem M, Ren A, Feichtinger K, Al Doori B, Wei J, Wu C, Dang H, Le M, Gatlin J, Chase K, Dong J, Whelan KT, Sage C, Grottick AJ, Semple G.
Abstract : The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
|
Agonist activity at recombinant human 5-HT2B receptor expressed in HEK293E cells assessed as induction of intracellular Ca2+ levels after 90 secs by Fluo-4-dye based FLIPR assay
|
Homo sapiens
|
287.0
nM
|
|
Journal : J Med Chem
Title : Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists.
Year : 2017
Volume : 60
Issue : 14
First Page : 6166
Last Page : 6190
Authors : Carpenter J, Wang Y, Wu G, Feng J, Ye XY, Morales CL, Broekema M, Rossi KA, Miller KJ, Murphy BJ, Wu G, Malmstrom SE, Azzara AV, Sher PM, Fevig JM, Alt A, Bertekap RL, Cullen MJ, Harper TM, Foster K, Luk E, Xiang Q, Grubb MF, Robl JA, Wacker DA.
Abstract : Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
|
Agonist activity at recombinant human 5-HT2A receptor expressed in HEK293E cells assessed as induction of intracellular Ca2+ levels after 90 secs by Fluo-4-dye based FLIPR assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J Med Chem
Title : Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists.
Year : 2017
Volume : 60
Issue : 14
First Page : 6166
Last Page : 6190
Authors : Carpenter J, Wang Y, Wu G, Feng J, Ye XY, Morales CL, Broekema M, Rossi KA, Miller KJ, Murphy BJ, Wu G, Malmstrom SE, Azzara AV, Sher PM, Fevig JM, Alt A, Bertekap RL, Cullen MJ, Harper TM, Foster K, Luk E, Xiang Q, Grubb MF, Robl JA, Wacker DA.
Abstract : Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
|
Agonist activity at recombinant human 5-HT2C receptor expressed in HEK293E cells assessed as induction of intracellular Ca2+ levels after 90 secs by Fluo-4-dye based FLIPR assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : J Med Chem
Title : Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists.
Year : 2017
Volume : 60
Issue : 14
First Page : 6166
Last Page : 6190
Authors : Carpenter J, Wang Y, Wu G, Feng J, Ye XY, Morales CL, Broekema M, Rossi KA, Miller KJ, Murphy BJ, Wu G, Malmstrom SE, Azzara AV, Sher PM, Fevig JM, Alt A, Bertekap RL, Cullen MJ, Harper TM, Foster K, Luk E, Xiang Q, Grubb MF, Robl JA, Wacker DA.
Abstract : Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.46
%
|
|
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
|
-0.1
%
|
|
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
|
-0.1
%
|
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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.
