|
Displacement of [3H]8-OH-DPAT from 5-hydroxytryptamine 1A receptor of rat hippocampal membranes
|
Rattus norvegicus
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Displacement of [3H]8-OH-DPAT from 5-hydroxytryptamine 1A receptor of bovine hippocampus.
|
Bos taurus
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.
Year : 1993
Volume : 36
Issue : 15
First Page : 2066
Last Page : 2074
Authors : Romero AG, Leiby JA, McCall RB, Piercey MF, Smith MW, Han F.
Abstract : The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in vivo models was (R)-14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.
|
Binding affinity of compound towards 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT (0.5 nM) ligand in hippocampus + frontal bovine was determined
|
None
|
8.6
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Ability to displace [3H]-DPAT from 5-hydroxytryptamine 1A receptor in homogenates of bovine hippocampus.
|
None
|
6.6
nM
|
|
Journal : J. Med. Chem.
Title : Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.
Year : 1992
Volume : 35
Issue : 6
First Page : 1076
Last Page : 1092
Authors : Moon MW, Morris JK, Heier RF, Chidester CG, Hoffmann WE, Piercey MF, Althaus JS, Von Voigtlander PF, Evans DL, Figur LM.
Abstract : The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
|
In vitro binding affinity against 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT in human CYP3A4 assay
|
None
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design and preparation of metabolically protected new arylpiperazine 5-HT1A ligands.
Year : 2004
Volume : 14
Issue : 7
First Page : 1709
Last Page : 1712
Authors : Tandon M, O'Donnell MM, Porte A, Vensel D, Yang D, Palma R, Beresford A, Ashwell MA.
Abstract : New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT(1A) affinity and potential sites of metabolism by human cytochrome p450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT(1A) affinity and CYP3A4 stability are described.
|
Binding affinity towards rat 5-hydroxytryptamine 1A receptor was evaluated using [3H]8-OH-DPAT as radioligand
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on the 5-HT(1A) receptor affinity of 1-phenyl-4-[omega-(alpha- or beta-tetralinyl)alkyl]piperazines. 4.
Year : 1996
Volume : 39
Issue : 25
First Page : 4928
Last Page : 4934
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis of 1-phenylpiperazines, linked in the alpha or beta position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT(2A), D-1, D-2, alpha1, and alpha2 receptors along with SAR studies on the 5-HT(1A) receptor are reported. Several changes have been carried out on previous structures of type 2, by inserting the alkyl chain with variable length in the alpha or beta position of the tetralin moiety and by changing the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest affinity (IC50 = 0.50 nM) and selectivity for the 5-HT(1A) receptor were showed by 1-phenylpiperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the omega position.
|
Binding affinity against 5-hydroxytryptamine 1A receptor in rat hippocampus membranes using [3H]8-OH-DPAT as radioligand
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-aryl-4-[(1-tetralinyl)alkyl]piperazines: alkylamido and alkylamino derivatives. Synthesis, 5-HT1A receptor affinity, and selectivity. 3.
Year : 1996
Volume : 39
Issue : 16
First Page : 3195
Last Page : 3202
Authors : Perrone R, Berardi F, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis and binding profile on 5-HT1A, 5-HT2, D-1, D-2, alpha 1, and alpha 2 receptors of the N-4 long-chain arylpiperazines 22-40 are reported, where an amino or amido function is inserted into the intermediate chain linked to the alpha position of the tetralin nucleus. Unlike the buspirone analogues, for the amido derivatives studied in this paper, the terminal amide function of long-chain piperazines is not important for 5-HT1A receptor affinity binding, and its removal yields high-affinity 5-HT1A receptor agents.
|
Binding affinity to 5-hydroxytryptamine 1A receptor of rat hippocampus with [3H]8-OH-DPAT as radioligand
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New 5-HT1A receptor agonists possessing 1,4-benzoxazepine scaffold exhibit highly potent anti-ischemic effects.
Year : 2001
Volume : 11
Issue : 4
First Page : 595
Last Page : 598
Authors : Kamei K, Maeda N, Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T.
Abstract : A series of new 3-substituted-4-(4-aminobutyl)-1,4-benzoxazepin-5(4H)-one derivatives (1-5) which showed a very high affinity for 5-HT1A receptor with good selectivity over dopamine D2 receptor was synthesized. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1,4-benzoxazepin-5(4H)-one (5: SUN N4057) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
|
Binding affinity against 5-hydroxytryptamine 1A (5-HT1A) receptor in rat hippocampus membranes
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : 3,4-Dihydro-3-amino-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 1. Synthesis and structure--activity relationship studies.
Year : 1994
Volume : 37
Issue : 12
First Page : 1779
Last Page : 1793
Authors : Podona T, Guardiola-Lemaître B, Caignard DH, Adam G, Pfeiffer B, Renard P, Guillaumet G.
Abstract : A series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives were prepared in order to determine the necessary structural requirements for good affinity for 5-HT1A receptors and high selectivity versus other receptors. Modifications of the extracyclic amino substituents, the length of the alkyl side chains, and their substituents were explored. The best compounds (9g, 9k, 15b, 15d) possess imido or sulfonamido functional groups with a preferential length of four methylenes for the side chain. After resolution, the dextrorotatory enantiomers showed better affinity and selectivity for 5-HT1A receptors. These compounds have been proven to be full agonists. 9g and its enantiomers showed anxiolytic activity in vivo in various comportemental models. The compound (+)-9g is currently under clinical investigation.
|
Binding affinity to 5-hydroxytryptamine 1A receptor in rat hippocampus membranes,3H-8-OH-DPAT and buspirone for nonspecific binding (NSB)
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans]
Year : 1996
Volume : 39
Issue : 21
First Page : 4285
Last Page : 4298
Authors : Comoy C, Marot C, Podona T, Baudin ML, Morin-Allory L, Guillaumet G, Pfeiffer B, Caignard DH, Renard P, Rettori MC, Adam G, Guardiola-Lemaitre B.
Abstract : In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.
|
In vitro inhibition of [3H]8-OH-DPAT binding to rat 5-HT 1a receptors.
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)alkyl]piperazines and their analogues: influence of the stereochemistry of the tetrahydronaphthalen-1-yl nucleus on 5-HT1A receptor affinity and selectivity versus alpha1 and D2 receptors. 5.
Year : 1999
Volume : 42
Issue : 3
First Page : 490
Last Page : 496
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V.
Abstract : Some 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their absolute configuration was determined by chemical correlation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and alpha1 receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicated that, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between (-)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry, instead, influenced the selectivity: all (-)-enantiomers displayed affinity values higher than those of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinity values higher than those of (-)-isomers at alpha1 receptors. As a result of this trend, it is not possible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (>/=250-fold) versus both D2 and alpha1 receptors. Furthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [35S]GTPgammaS binding assay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.
|
In vitro ability to inhibit binding of radioligand [3H]8-OH-DPAT to 5-hydroxytryptamine 1A receptor in rat cerebral cortex
|
None
|
12.8
nM
|
|
Journal : J. Med. Chem.
Title : Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.
Year : 1994
Volume : 37
Issue : 1
First Page : 99
Last Page : 104
Authors : Perrone R, Berardi F, Colabufo NA, Tortorella V, Fiorentini F, Olgiati V, Vanotti E, Govoni S.
Abstract : A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.
|
In vitro binding affinity measured on serotonin 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT as radioligand.
|
None
|
12.8
nM
|
|
Journal : J. Med. Chem.
Title : High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.
Year : 1995
Volume : 38
Issue : 6
First Page : 942
Last Page : 949
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fiorentini F, Olgiati V, Ghiglieri A, Govoni S.
Abstract : Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.
|
In vitro binding affinity towards the 5-hydroxytryptamine 1A receptor was evaluated
|
None
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors.
Year : 1993
Volume : 36
Issue : 10
First Page : 1509
Last Page : 1510
Authors : Cliffe IA, Brightwell CI, Fletcher A, Forster EA, Mansell HL, Reilly Y, Routledge C, White AC.
|
Inhibition of forskolin-activated adenylate cyclase (cAMP) activity at 5-hydroxytryptamine 1A receptor in rat hippocampus
|
None
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Binding affinity against human 5-hydroxytryptamine 1A receptor
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Binding affinity for 5-hydroxytryptamine 1A receptor with [3H]5-HT
|
Rattus norvegicus
|
46.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure activity relationships of cis- and trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-c]pyridines for 5-HT receptor subtypes.
Year : 1994
Volume : 37
Issue : 1
First Page : 105
Last Page : 112
Authors : Meyer MD, DeBernardis JF, Hancock AA.
Abstract : A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
|
Binding affinity by measuring displacement of [3H]8-OH-DPAT from 5-hydroxytryptamine 1A receptor in rat hippocampus
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : (R)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines: novel optically active compounds with strong 5-HT1A receptor binding ability exhibiting anticonflict activity and lessening of memory impairment.
Year : 1993
Volume : 36
Issue : 23
First Page : 3526
Last Page : 3532
Authors : Kawakubo H, Takagi S, Yamaura Y, Katoh S, Ishimoto Y, Nagatani T, Mochizuki D, Kamata T, Sasaki Y.
Abstract : (R)-1,2,3,4-Tetrahydro[1]benzothieno[2,3-c]pyridine derivatives (60-114) were synthesized. The (R)-isomers have affinity for the 5-HT1A receptor while the (S)-isomers have no such ability. The affinity of the (R)-isomers was discussed on the basis of structure-activity relationships between the affinity and hydrophobicity of the (R)-isomers. Compounds 71 and 107, which are representative derivative compounds, have anticonflict activity and lessening of memory impairment. In particular, compound 107 cannot bind to receptors other than the 5-HT1A receptor, demonstrating that it is a unique compound with a different mechanism of action from that of conventional anxiolytics.
|
Binding affinity towards 5-hydroxytryptamine 1A receptor in the rat brain (hippocampus) using [3H]8-OH-DPAT
|
Rattus norvegicus
|
12.3
nM
|
|
Journal : J. Med. Chem.
Title : 8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl]butyl-8-azaspiro[4.5]decane-7,9-dione: a new 5-HT1A receptor ligand with the same activity profile as buspirone.
Year : 1996
Volume : 39
Issue : 5
First Page : 1125
Last Page : 1129
Authors : Mokrosz JL, Dereń-Wesołek A, Tatarczyńska E, Duszyńska B, Bojarski AJ, Mokrosz MJ, Chojnacka-Wójcik E.
Abstract : A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors.
|
Binding affinity against rat hippocampal 5-hydroxytryptamine 1A (5-HT1A) receptor determined using [3H]8-OH-DPAT as radioligand
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Binding was determined on 5-hydroxytryptamine 1A receptor in rat hippocampal membranes
|
None
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: a new class of potent and selective 5-HT(1A) receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines.
Year : 2001
Volume : 44
Issue : 25
First Page : 4431
Last Page : 4442
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Lacivita E, Tortorella V, Leonardi A, Poggesi E, Testa R.
Abstract : The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.
|
Binding affinity was determined against 5-hydroxytryptamine 1A receptor using [3H]WB-4101
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Piperazinylalkyl heterocycles as potential antipsychotic agents.
Year : 1995
Volume : 38
Issue : 21
First Page : 4198
Last Page : 4210
Authors : Scott MK, Baxter EW, Bennett DJ, Boyd RE, Blum PS, Codd EE, Kukla MJ, Malloy E, Maryanoff BE, Maryanoff CA.
Abstract : We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.
|
Binding affinity at 5-hydroxytryptamine 1A receptor in rat cerebral cortex membranes by [3H]8-OH-DPAT displacement.
|
None
|
20.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-[4-(o-methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
Year : 1996
Volume : 6
Issue : 6
First Page : 689
Last Page : 694
Authors : Lopez-Rodriguez ML, Morcillo M, Rosado M, Benhamu B, Sanz AM
|
Binding affinity towards rat 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT radioligand.
|
None
|
20.5
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-OH-DPAT from 5-hydroxytryptamine 1A receptor sites of rat brain cortex.
|
None
|
15.4
nM
|
|
Journal : J. Med. Chem.
Title : New (2-methoxyphenyl)piperazine derivatives as 5-HT1A receptor ligands with reduced alpha 1-adrenergic activity. Synthesis and structure-affinity relationships.
Year : 1995
Volume : 38
Issue : 8
First Page : 1273
Last Page : 1277
Authors : Orjales A, Alonso-Cires L, Labeaga L, Corcóstegui R.
Abstract : New 2-(methoxyphenyl)piperazine derivatives 1 and 2 containing a terminal heteroaryl or cycloalkyl amide fragment were prepared and their 5-HT1A affinities evaluated by radioligand binding assays. The influence of the alkyl chain length or the amide group on affinity was evaluated. A four-carbon chain appears to be optimal when the amide fragment is a heteroaryl group. Derivatives with a cycloalkyl moiety displayed maximum affinity in the two methylene chain series. Electronic distribution within the amide region seems to have an influence on affinity in heteroaryl derivatives. Replacement of the heteroaryl moiety by a cycloalkyl group led to compounds with enhanced affinity. Increasing the lipophilicity of the cycloalkyl derivatives by annelation and/or saturation increased their affinity for the 5-HT1A sites. Compounds with cis-bicyclo[3.3.0]octane (2a, 2c), norbornane (2f, 2g), and norbornene (2h, 2i) groups bind at 5-HT1A sites with 2-10-fold higher affinity than NAN-190. Antagonist activity at alpha 1-adrenergic receptors was evaluated for compounds with high affinity at 5-HT1A sites. Compounds 2a, 2c, 2f, 2g, and 2h strongly bind (Ki = 0.12-0.63 nM) at 5-HT1A receptors and are devoid of antagonist activity at alpha 1-adrenergic receptors.
|
In vitro ability to inhibit [3H]8-OH-DPAT binding to 5-hydroxytryptamine 1A receptor of rat hippocampus
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
Year : 1989
Volume : 32
Issue : 5
First Page : 1024
Last Page : 1033
Authors : Abou-Gharbia M, Moyer JA, Patel U, Webb M, Schiehser G, Andree T, Haskins JT.
Abstract : Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
|
Evaluated for binding affinity towards 5-hydroxytryptamine 1A receptor in rat brain
|
None
|
15.0
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 towards 5-hydroxytryptamine 1A receptor using receptor binding assay
|
None
|
7.13
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel pyridazino[4,5-b][1,5]oxazepines and -thiazepines as 5-HT1A receptor ligands
Year : 1997
Volume : 7
Issue : 22
First Page : 2857
Last Page : 2862
Authors : Matyus P, Varga I, Zara E, Mezei A, Behr A, Simay A, Haider N, Boros S, Bakonyi A, Horvath E, Horvath K
|
Effect against 5-hydroxytryptamine 1A receptor mediated inhibition of VIP-stimulated cAMP production at 0.1 uM dose
|
Rattus norvegicus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Effect on 5-hydroxytryptamine 1A receptor mediated inhibition of VIP-stimulated cAMP production at dose of 0.1 uM + 1 uM 5-HT.
|
None
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Effect on 5-hydroxytryptamine 1A receptor mediated inhibition of VIP-stimulated cAMP production at dose of 10 uM
|
None
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Effect on 5-hydroxytryptamine 1A receptor mediated inhibition of VIP-stimulated cAMP production at dose of 1 uM
|
None
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Effect on 5-hydroxytryptamine 1A receptor mediated inhibition of VIP-stimulated cAMP production at dose of 1 uM+ 10 uM 5-HT.
|
None
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
Year : 1996
Volume : 39
Issue : 20
First Page : 4036
Last Page : 4043
Authors : Höök BB, Cortizo L, Johansson AM, Westlind-Danielsson A, Mohell N, Hacksell U.
Abstract : Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
|
Binding affinity against rat 5-hydroxytryptamine 1A receptor
|
None
|
9.3
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
In vitro inhibition of [3H]spiperone binding to 5-hydroxytryptamine 1A receptor from rat hippocampal tissue.
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies.
Year : 1988
Volume : 31
Issue : 7
First Page : 1382
Last Page : 1392
Authors : Abou-Gharbia M, Patel UR, Webb MB, Moyer JA, Andree TH, Muth EA.
Abstract : A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.
|
Antagonist activity against rat hippocampal tissue 5-hydroxytryptamine 1A receptor
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.
Year : 1999
Volume : 42
Issue : 25
First Page : 5077
Last Page : 5094
Authors : Abou-Gharbia MA, Childers WE, Fletcher H, McGaughey G, Patel U, Webb MB, Yardley J, Andree T, Boast C, Kucharik RJ, Marquis K, Morris H, Scerni R, Moyer JA.
Abstract : Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
|
Inhibitory affinity constant against 5-hydroxytryptamine 1A receptor
|
None
|
13.8
nM
|
|
Journal : J. Med. Chem.
Title : Buspirone analogues as ligands of the 5-HT1A receptor. 1. The molecular structure of buspirone and its two analogues.
Year : 1995
Volume : 38
Issue : 10
First Page : 1701
Last Page : 1710
Authors : Chilmonczyk Z, Leś A, Woźniakowska A, Cybulski J, Kozioł AE, Gdaniec M.
Abstract : An interdisciplinary (X-ray, 1H and 13C NMR, IR, and theoretical quantum mechanical) study on the potent 5-HT1A receptor ligand buspirone (1) and its two structural analogues, mesmar (4,4-dimethyl-1-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) (2) and kaspar (8-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane - 7,9-dione) (3), has been reported. The results have shown that buspirone-like molecules should appear in an extended rod-shape form, possessing several potential interaction sites with the receptor.
|
Binding affinity towards 5-hydroxytryptamine 1A receptor by displacing [3H]WB-4101 from rat hippocampus
|
Rattus norvegicus
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Binding affinity towards 5-hydroxytryptamine 1A receptor in rat brain membrane using [3H]8-OH-DPAT as a selective ligand.
|
None
|
21.88
nM
|
|
Journal : J. Med. Chem.
Title : Graphics computer-aided receptor mapping as a predictive tool for drug design: development of potent, selective, and stereospecific ligands for the 5-HT1A receptor.
Year : 1988
Volume : 31
Issue : 6
First Page : 1087
Last Page : 1093
Authors : Hibert MF, Gittos MW, Middlemiss DN, Mir AK, Fozard JR.
Abstract : A conformational study of four 5-HT1A (serotonin) receptor ligands ((R-(-)-methiothepin, spiperone, (S)-(-)-propranolol, and buspirone) led to the definition of a pharmacophore and a three-dimensional map of the 5-HT1A antagonist recognition site. These models were used to design new compounds and successfully predict their potency, stereospecificity, and selectivity. For example, 8-[4-[(1,4-benzodioxan-2-ylmethyl)amino] butyl]-8-azaspiro[4.5]decane-7,9-dione (1, MDL 72832) has nanomolar affinity (pIC50 = 9.14) for the 5-HT1A binding site in rat frontal cortex. As predicted, the S-(-) enantiomer of 1 was more active than its R-(+) enantiomer (pIC50 = 9.21 and 7.66, respectively) and a naphthalene analogue of 1 displayed the expected improved selectivity.
|
Binding affinity of a compound to rat brain 5-hydroxytryptamine 1A (serotonin) receptor assayed by radiolabeled [3H]-8-OH-DPAT ligand displacement
|
None
|
19.95
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.
|
In vitro ability to inhibit binding of radioligand [3H]8-OH-DPAT to 5-hydroxytryptamine 1A receptor in rat cerebral cortex
|
None
|
14.79
nM
|
|
Journal : J. Med. Chem.
Title : Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.
Year : 1994
Volume : 37
Issue : 1
First Page : 99
Last Page : 104
Authors : Perrone R, Berardi F, Colabufo NA, Tortorella V, Fiorentini F, Olgiati V, Vanotti E, Govoni S.
Abstract : A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.
|
Inhibition of [3H]5-HT binding to 5-hydroxytryptamine 1B receptor
|
Rattus norvegicus
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure activity relationships of cis- and trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-c]pyridines for 5-HT receptor subtypes.
Year : 1994
Volume : 37
Issue : 1
First Page : 105
Last Page : 112
Authors : Meyer MD, DeBernardis JF, Hancock AA.
Abstract : A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
|
In vitro binding affinity measured on serotonin 5-hydroxytryptamine 2 receptor using [3H]ketanserin as radioligand.
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.
Year : 1995
Volume : 38
Issue : 6
First Page : 942
Last Page : 949
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fiorentini F, Olgiati V, Ghiglieri A, Govoni S.
Abstract : Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.
|
Binding affinity against 5-hydroxytryptamine 2 receptor
|
None
|
178.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Displacement of [3H]ketanserin from 5-hydroxytryptamine 2 receptor
|
Rattus norvegicus
|
391.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure activity relationships of cis- and trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-c]pyridines for 5-HT receptor subtypes.
Year : 1994
Volume : 37
Issue : 1
First Page : 105
Last Page : 112
Authors : Meyer MD, DeBernardis JF, Hancock AA.
Abstract : A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
|
The compound was tested for its binding affinity towards 5-hydroxytryptamine 2 receptor by displacing [3H]ketanserin radioligand in rat cerebral cortex
|
None
|
174.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Compound was evaluated for binding affinity against 5-hydroxytryptamine 2A receptor using [3H]ketanserin as a radioligand
|
None
|
482.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-[4-(o-methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
Year : 1996
Volume : 6
Issue : 6
First Page : 689
Last Page : 694
Authors : Lopez-Rodriguez ML, Morcillo M, Rosado M, Benhamu B, Sanz AM
|
Compound was evaluated for the binding affinity towards 5-hydroxytryptamine 2A receptor using [3H]-ketanserin radioligand.
|
None
|
482.0
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.
|
Binding affinity towards alpha-1 adrenergic receptor using [3H]prazosin radioligand.
|
None
|
367.0
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.
|
The compound was tested for its binding affinity towards Alpha-1 adrenergic receptor by displacing [3H]WB-4101 radioligand in rat cerebral cortex
|
None
|
138.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Percent inhibition of Alpha-1 adrenergic receptor by 1 uM of compound
|
None
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
Year : 1989
Volume : 32
Issue : 5
First Page : 1024
Last Page : 1033
Authors : Abou-Gharbia M, Moyer JA, Patel U, Webb M, Schiehser G, Andree T, Haskins JT.
Abstract : Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
|
Antagonistic activity at Alpha-1 adrenergic receptor was performed on ring segments of rabbit thoracic aorta contracted by noradrenaline.
|
Oryctolagus cuniculus
|
575.44
nM
|
|
Journal : J. Med. Chem.
Title : New (2-methoxyphenyl)piperazine derivatives as 5-HT1A receptor ligands with reduced alpha 1-adrenergic activity. Synthesis and structure-affinity relationships.
Year : 1995
Volume : 38
Issue : 8
First Page : 1273
Last Page : 1277
Authors : Orjales A, Alonso-Cires L, Labeaga L, Corcóstegui R.
Abstract : New 2-(methoxyphenyl)piperazine derivatives 1 and 2 containing a terminal heteroaryl or cycloalkyl amide fragment were prepared and their 5-HT1A affinities evaluated by radioligand binding assays. The influence of the alkyl chain length or the amide group on affinity was evaluated. A four-carbon chain appears to be optimal when the amide fragment is a heteroaryl group. Derivatives with a cycloalkyl moiety displayed maximum affinity in the two methylene chain series. Electronic distribution within the amide region seems to have an influence on affinity in heteroaryl derivatives. Replacement of the heteroaryl moiety by a cycloalkyl group led to compounds with enhanced affinity. Increasing the lipophilicity of the cycloalkyl derivatives by annelation and/or saturation increased their affinity for the 5-HT1A sites. Compounds with cis-bicyclo[3.3.0]octane (2a, 2c), norbornane (2f, 2g), and norbornene (2h, 2i) groups bind at 5-HT1A sites with 2-10-fold higher affinity than NAN-190. Antagonist activity at alpha 1-adrenergic receptors was evaluated for compounds with high affinity at 5-HT1A sites. Compounds 2a, 2c, 2f, 2g, and 2h strongly bind (Ki = 0.12-0.63 nM) at 5-HT1A receptors and are devoid of antagonist activity at alpha 1-adrenergic receptors.
|
Binding affinity at Alpha-1 adrenergic receptor in rat cerebral cortex membranes by [3H]prazosin displacement.
|
None
|
367.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-[4-(o-methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
Year : 1996
Volume : 6
Issue : 6
First Page : 689
Last Page : 694
Authors : Lopez-Rodriguez ML, Morcillo M, Rosado M, Benhamu B, Sanz AM
|
Percent inhibition of GABA-A benzodiazepine receptor at 1 uM
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
Year : 1989
Volume : 32
Issue : 5
First Page : 1024
Last Page : 1033
Authors : Abou-Gharbia M, Moyer JA, Patel U, Webb M, Schiehser G, Andree T, Haskins JT.
Abstract : Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
|
Percent inhibition of Beta adrenergic receptor by 1 uM of compound
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
Year : 1989
Volume : 32
Issue : 5
First Page : 1024
Last Page : 1033
Authors : Abou-Gharbia M, Moyer JA, Patel U, Webb M, Schiehser G, Andree T, Haskins JT.
Abstract : Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
|
Binding affinity for DA2 receptor
|
None
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : (R)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines: novel optically active compounds with strong 5-HT1A receptor binding ability exhibiting anticonflict activity and lessening of memory impairment.
Year : 1993
Volume : 36
Issue : 23
First Page : 3526
Last Page : 3532
Authors : Kawakubo H, Takagi S, Yamaura Y, Katoh S, Ishimoto Y, Nagatani T, Mochizuki D, Kamata T, Sasaki Y.
Abstract : (R)-1,2,3,4-Tetrahydro[1]benzothieno[2,3-c]pyridine derivatives (60-114) were synthesized. The (R)-isomers have affinity for the 5-HT1A receptor while the (S)-isomers have no such ability. The affinity of the (R)-isomers was discussed on the basis of structure-activity relationships between the affinity and hydrophobicity of the (R)-isomers. Compounds 71 and 107, which are representative derivative compounds, have anticonflict activity and lessening of memory impairment. In particular, compound 107 cannot bind to receptors other than the 5-HT1A receptor, demonstrating that it is a unique compound with a different mechanism of action from that of conventional anxiolytics.
|
Binding affinity towards rat Dopamine receptor D2 was evaluated using [3H]- spiroperidol as radioligand
|
None
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on the 5-HT(1A) receptor affinity of 1-phenyl-4-[omega-(alpha- or beta-tetralinyl)alkyl]piperazines. 4.
Year : 1996
Volume : 39
Issue : 25
First Page : 4928
Last Page : 4934
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis of 1-phenylpiperazines, linked in the alpha or beta position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT(2A), D-1, D-2, alpha1, and alpha2 receptors along with SAR studies on the 5-HT(1A) receptor are reported. Several changes have been carried out on previous structures of type 2, by inserting the alkyl chain with variable length in the alpha or beta position of the tetralin moiety and by changing the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest affinity (IC50 = 0.50 nM) and selectivity for the 5-HT(1A) receptor were showed by 1-phenylpiperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the omega position.
|
Binding affinity against Dopamine receptor D2 in rat striatal membrane using [3H]spiroperidol as radioligand
|
None
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-aryl-4-[(1-tetralinyl)alkyl]piperazines: alkylamido and alkylamino derivatives. Synthesis, 5-HT1A receptor affinity, and selectivity. 3.
Year : 1996
Volume : 39
Issue : 16
First Page : 3195
Last Page : 3202
Authors : Perrone R, Berardi F, Leopoldo M, Tortorella V, Fornaretto MG, Caccia C, McArthur RA.
Abstract : The synthesis and binding profile on 5-HT1A, 5-HT2, D-1, D-2, alpha 1, and alpha 2 receptors of the N-4 long-chain arylpiperazines 22-40 are reported, where an amino or amido function is inserted into the intermediate chain linked to the alpha position of the tetralin nucleus. Unlike the buspirone analogues, for the amido derivatives studied in this paper, the terminal amide function of long-chain piperazines is not important for 5-HT1A receptor affinity binding, and its removal yields high-affinity 5-HT1A receptor agents.
|
Binding affinity to Dopamine receptor D2 in of rat striatum membrane with [3H]- raclopride as radioligand
|
None
|
55.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New 5-HT1A receptor agonists possessing 1,4-benzoxazepine scaffold exhibit highly potent anti-ischemic effects.
Year : 2001
Volume : 11
Issue : 4
First Page : 595
Last Page : 598
Authors : Kamei K, Maeda N, Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T.
Abstract : A series of new 3-substituted-4-(4-aminobutyl)-1,4-benzoxazepin-5(4H)-one derivatives (1-5) which showed a very high affinity for 5-HT1A receptor with good selectivity over dopamine D2 receptor was synthesized. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1,4-benzoxazepin-5(4H)-one (5: SUN N4057) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
|
Inhibition of [3H]raclopride binding to Dopamine receptor D2 of bovine striatum
|
Bos taurus
|
44.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Inhibition of [3H]spiperone binding to dopamine receptor from rat corpus striatal membranes
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives.
Year : 1983
Volume : 26
Issue : 2
First Page : 194
Last Page : 203
Authors : Yevich JP, Temple DL, New JS, Taylor DP, Riblet LA.
Abstract : A series of analogues of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length, and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the alpha 1-adrenergic antagonist [3H]WB-4101. Compounds were also tested in vivo for tranquilizing properties and induction of catalepsy. Potency at the [3H]spiperone binding site was affected by alkylene chain length and imide portion composition. Nonortho substituents on the aryl moiety had little effect on [3H]spiperone binding affinity. Structure-activity relationships of ortho substituents demonstrated only modest correlations between the receptor binding data and physical parameters of the substituents. The complex nature of the drug-receptor interactions may be understood in terms of the fit of buspirone to a hypothetical model of the dopamine receptor.
|
Displacement of [3H]U-86170 from human D2-dopamine receptor expressed in CHO K1 cells
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.
Year : 1993
Volume : 36
Issue : 15
First Page : 2066
Last Page : 2074
Authors : Romero AG, Leiby JA, McCall RB, Piercey MF, Smith MW, Han F.
Abstract : The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in vivo models was (R)-14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.
|
In vitro ability to inhibit binding of radioligand [3H]spiroperidol to dopamine D2 receptor in rat striatal membrane
|
None
|
41.69
nM
|
|
Journal : J. Med. Chem.
Title : Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.
Year : 1994
Volume : 37
Issue : 1
First Page : 99
Last Page : 104
Authors : Perrone R, Berardi F, Colabufo NA, Tortorella V, Fiorentini F, Olgiati V, Vanotti E, Govoni S.
Abstract : A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.
|
Inhibition of binding of radioligand [3H]spiroperidol to dopamine D2 receptor in rat striatal membranes
|
None
|
222.0
nM
|
|
Journal : J. Med. Chem.
Title : Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.
Year : 1994
Volume : 37
Issue : 1
First Page : 99
Last Page : 104
Authors : Perrone R, Berardi F, Colabufo NA, Tortorella V, Fiorentini F, Olgiati V, Vanotti E, Govoni S.
Abstract : A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.
|
In vitro binding affinity measured on dopamine receptor D2 using [3H]spiroperidol as radioligand.
|
None
|
226.0
nM
|
|
Journal : J. Med. Chem.
Title : High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.
Year : 1995
Volume : 38
Issue : 6
First Page : 942
Last Page : 949
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fiorentini F, Olgiati V, Ghiglieri A, Govoni S.
Abstract : Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.
|
In vitro binding affinity towards the dopamine receptor D2 at 10 e-6 M
|
None
|
265.0
nM
|
|
Journal : J. Med. Chem.
Title : (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors.
Year : 1993
Volume : 36
Issue : 10
First Page : 1509
Last Page : 1510
Authors : Cliffe IA, Brightwell CI, Fletcher A, Forster EA, Mansell HL, Reilly Y, Routledge C, White AC.
|
Inhibition of [3H]spiperone binding to Dopamine receptor D3 in bovine cortex
|
Bos taurus
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Binding affinity was determined against Dopamine receptor D2 using [3H]spiperone
|
None
|
367.0
nM
|
|
Journal : J. Med. Chem.
Title : Piperazinylalkyl heterocycles as potential antipsychotic agents.
Year : 1995
Volume : 38
Issue : 21
First Page : 4198
Last Page : 4210
Authors : Scott MK, Baxter EW, Bennett DJ, Boyd RE, Blum PS, Codd EE, Kukla MJ, Malloy E, Maryanoff BE, Maryanoff CA.
Abstract : We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.
|
Compound was evaluated for binding affinity against Dopamine receptor D2 using [3H]raclopride as a radioligand
|
None
|
852.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-[4-(o-methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
Year : 1996
Volume : 6
Issue : 6
First Page : 689
Last Page : 694
Authors : Lopez-Rodriguez ML, Morcillo M, Rosado M, Benhamu B, Sanz AM
|
Binding affinity towards dopamine receptor D2 using [3H]-raclopride radioligand.
|
None
|
852.0
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 inhibit [3H]spiperone binding to dopamine receptor D2 of rat limbic structures
|
None
|
119.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.
Year : 1989
Volume : 32
Issue : 5
First Page : 1024
Last Page : 1033
Authors : Abou-Gharbia M, Moyer JA, Patel U, Webb M, Schiehser G, Andree T, Haskins JT.
Abstract : Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
|
In vitro inhibition of [3H]spiperone binding to Dopamine receptor D2 from rat brain limbic tissue
|
None
|
119.0
nM
|
|
Journal : J. Med. Chem.
Title : Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies.
Year : 1988
Volume : 31
Issue : 7
First Page : 1382
Last Page : 1392
Authors : Abou-Gharbia M, Patel UR, Webb MB, Moyer JA, Andree TH, Muth EA.
Abstract : A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.
|
Inhibitory activity against rat limbic tissue Dopamine receptor D2
|
None
|
119.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.
Year : 1999
Volume : 42
Issue : 25
First Page : 5077
Last Page : 5094
Authors : Abou-Gharbia MA, Childers WE, Fletcher H, McGaughey G, Patel U, Webb MB, Yardley J, Andree T, Boast C, Kucharik RJ, Marquis K, Morris H, Scerni R, Moyer JA.
Abstract : Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.
|
Binding affinity towards dopamine receptor D2 by displacing [3H]spiperone radioligand in rat striatum
|
None
|
367.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Neuronal protective effect of compound against ischemic brain damage in rat t-MCAO model
|
Rattus norvegicus
|
53.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New 5-HT1A receptor agonists possessing 1,4-benzoxazepine scaffold exhibit highly potent anti-ischemic effects.
Year : 2001
Volume : 11
Issue : 4
First Page : 595
Last Page : 598
Authors : Kamei K, Maeda N, Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T.
Abstract : A series of new 3-substituted-4-(4-aminobutyl)-1,4-benzoxazepin-5(4H)-one derivatives (1-5) which showed a very high affinity for 5-HT1A receptor with good selectivity over dopamine D2 receptor was synthesized. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1,4-benzoxazepin-5(4H)-one (5: SUN N4057) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
|
The compound was tested for affinity towards sigma-3 receptor
|
None
|
36.31
nM
|
|
Journal : J. Med. Chem.
Title : Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.
Year : 1994
Volume : 37
Issue : 24
First Page : 4109
Last Page : 4117
Authors : Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD.
Abstract : Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.
|
In vitro binding affinity measured on sigma opioid receptor using [3H]DTG as radioligand
|
Cavia porcellus
|
263.0
nM
|
|
Journal : J. Med. Chem.
Title : High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.
Year : 1995
Volume : 38
Issue : 6
First Page : 942
Last Page : 949
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V, Fiorentini F, Olgiati V, Ghiglieri A, Govoni S.
Abstract : Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.
|
Inhibition of [3H]DTG binding to sigma receptor in rat hippocampus
|
Rattus norvegicus
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high-affinity sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 100 uM
|
Cavia porcellus
|
2.0
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Inhibitory concentration against Dopamine receptor D2 in rat striatum membrane using [3H]raclopride as radioligand
|
Rattus norvegicus
|
55.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects.
Year : 2005
Volume : 15
Issue : 12
First Page : 2990
Last Page : 2993
Authors : Kamei K, Maeda N, Katsuragi-Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T.
Abstract : A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
|
Inhibitory concentration against 5-hydroxytryptamine 1A receptor in rat hippocampus membrane using [3H]-8-OH-DPAT as radioligand
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects.
Year : 2005
Volume : 15
Issue : 12
First Page : 2990
Last Page : 2993
Authors : Kamei K, Maeda N, Katsuragi-Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T.
Abstract : A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
|
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor in HEK293 cells
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.
Year : 2006
Volume : 49
Issue : 11
First Page : 3116
Last Page : 3135
Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.
Abstract : We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
|
Displacement of [3H]prazosin from adrenergic alpha-1 receptor in rat cerebral cortex cells
|
Rattus norvegicus
|
367.0
nM
|
|
Journal : J. Med. Chem.
Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.
Year : 2006
Volume : 49
Issue : 11
First Page : 3116
Last Page : 3135
Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.
Abstract : We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
|
Binding affinity to D2 receptor by radioligand binding assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.
Year : 2006
Volume : 49
Issue : 11
First Page : 3116
Last Page : 3135
Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.
Abstract : We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
|
Activity against 5HT1A receptor by Gi-[35S]GTP-gamma-S binding assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.
Year : 2006
Volume : 49
Issue : 11
First Page : 3116
Last Page : 3135
Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.
Abstract : We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
|
Affinity for 5HT1A receptor
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Arylpiperazines with N-acylated amino acids as 5-HT1A receptor ligands.
Year : 2006
Volume : 16
Issue : 13
First Page : 3406
Last Page : 3410
Authors : Zajdel P, Subra G, Bojarski AJ, Duszyńska B, Pawłowski M, Martinez J.
Abstract : A library consisting of 60 arylpiperazines modified with N-acylated amino acids was prepared on BAL linker SynPhasetrade mark Lanterns and evaluated in vitro for 5-HT(1A) receptor affinity. Biological screening, followed by a simple Fujita-Ban analysis, enabled the description of structure-activity relationships and allowed the selection of some potent, high-affinity ligands for in vivo pharmacological investigations.
|
Displacement of [3H]8-OH-DPAT from 5HT1A receptor in CRL:CD(SD)BR-COBS rat hippocampus
|
Rattus norvegicus
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands.
Year : 2008
Volume : 51
Issue : 15
First Page : 4529
Last Page : 4538
Authors : Siracusa MA, Salerno L, Modica MN, Pittalà V, Romeo G, Amato ME, Nowak M, Bojarski AJ, Mereghetti I, Cagnotto A, Mennini T.
Abstract : A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.
|
Displacement of [3H]prazosin from adrenergic receptor alpha1 in CRL:CD(SD)BR-COBS rat brain cortex
|
Rattus norvegicus
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands.
Year : 2008
Volume : 51
Issue : 15
First Page : 4529
Last Page : 4538
Authors : Siracusa MA, Salerno L, Modica MN, Pittalà V, Romeo G, Amato ME, Nowak M, Bojarski AJ, Mereghetti I, Cagnotto A, Mennini T.
Abstract : A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
24.7
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of aminopyrimidine series of 5-HT1A partial agonists.
Year : 2009
Volume : 19
Issue : 4
First Page : 1159
Last Page : 1163
Authors : Dounay AB, Barta NS, Bikker JA, Borosky SA, Campbell BM, Crawford T, Denny L, Evans LM, Gray DL, Lee P, Lenoir EA, Xu W.
Abstract : Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
|
Agonist activity at human 5HT1A receptor expressed in CHO cells by FLIPR
|
Homo sapiens
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of aminopyrimidine series of 5-HT1A partial agonists.
Year : 2009
Volume : 19
Issue : 4
First Page : 1159
Last Page : 1163
Authors : Dounay AB, Barta NS, Bikker JA, Borosky SA, Campbell BM, Crawford T, Denny L, Evans LM, Gray DL, Lee P, Lenoir EA, Xu W.
Abstract : Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
|
Displacement of [3H]ketanserin from 5HT2A receptor
|
None
|
851.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and serotonin receptor activity of the arylpiperazine alkyl/propoxy derivatives of new azatricycloundecanes.
Year : 2009
Volume : 44
Issue : 1
First Page : 152
Last Page : 164
Authors : Bojarski AJ, Kuran B, Kossakowski J, Kozioł A, Jagiełło-Wójtowicz E, Chodkowska A.
Abstract : A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione, were synthesized and tested for their affinity for 5-HT(1A) and 5-HT(2A) receptors. The Fujita-Ban analysis showed that the influence of structural modifications on the affinity for both receptor subtypes is additive and that the activity of similar compounds could be predicted with high accuracy. Compounds 46, 48 and 18 out of 14 screened in a functional model of anxiety and depression demonstrated antidepressant activity in the forced swimming tests in mice, and were devoid of neurotoxic effects (chimney test in mice).
|
Displacement of [3H]8-OH-DPAT from 5HT1A receptor in rat hippocampal membranes
|
Rattus norvegicus
|
3.8
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and serotonin receptor activity of the arylpiperazine alkyl/propoxy derivatives of new azatricycloundecanes.
Year : 2009
Volume : 44
Issue : 1
First Page : 152
Last Page : 164
Authors : Bojarski AJ, Kuran B, Kossakowski J, Kozioł A, Jagiełło-Wójtowicz E, Chodkowska A.
Abstract : A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione, were synthesized and tested for their affinity for 5-HT(1A) and 5-HT(2A) receptors. The Fujita-Ban analysis showed that the influence of structural modifications on the affinity for both receptor subtypes is additive and that the activity of similar compounds could be predicted with high accuracy. Compounds 46, 48 and 18 out of 14 screened in a functional model of anxiety and depression demonstrated antidepressant activity in the forced swimming tests in mice, and were devoid of neurotoxic effects (chimney test in mice).
|
Displacement of [3H]8-OH-DPAT from 5HT1A receptor in rat hippocampal membrane
|
Rattus norvegicus
|
36.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : The influence of an ethylene spacer on the 5-HT(1A) and 5-HT(2A) receptor affinity of arylpiperazine derivatives of amides with N-acylated amino acids and 3-differently substituted pyrrolidine-2,5-diones.
Year : 2009
Volume : 44
Issue : 2
First Page : 800
Last Page : 808
Authors : Zajdel P, Subra G, Verdie P, Bojarski AJ, Duszyńska B, Basista K, Obniska J, Martinez J, Pawłowski M.
Abstract : A library of ethylene analogs of the previously described arylpiperazines with N-acylated amino acids was synthesized on SynPhase Lanterns and the library representatives were evaluated for their 5-HT(1A) and 5-HT(2A) receptor affinities. The obtained results were compared with those reported for compounds containing propylene and a butylene spacer and they revealed that 5-HT(1A) receptor affinity decreased proportionally with the length of the alkyl chain. Furthermore, the synthesized 3-cycloalkyl derivatives containing two methylene group spacers showed that the 3-position of pyrrolidine-2,5-dione preferred substituents of hydrophobic character.
|
Binding affinity to 5HT1A receptor
|
None
|
10.0
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.
|
Binding affinity to 5HT1A receptor
|
None
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of dihydrofuroaporphine derivatives: identification of a potent and selective serotonin 5-HT 1A receptor agonist.
Year : 2010
Volume : 53
Issue : 3
First Page : 1319
Last Page : 1328
Authors : Liu Z, Zhang H, Ye N, Zhang J, Wu Q, Sun P, Li L, Zhen X, Zhang A.
Abstract : A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.
|
Displacement of [3H]8-OH-DPAT from 5HT1A receptor expressed in CHO cells by liquid scintillation counting
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of dihydrofuroaporphine derivatives: identification of a potent and selective serotonin 5-HT 1A receptor agonist.
Year : 2010
Volume : 53
Issue : 3
First Page : 1319
Last Page : 1328
Authors : Liu Z, Zhang H, Ye N, Zhang J, Wu Q, Sun P, Li L, Zhen X, Zhang A.
Abstract : A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
4.81
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.
Year : 2009
Volume : 19
Issue : 23
First Page : 6793
Last Page : 6796
Authors : Vincent F, Nguyen MT, Emerling DE, Kelly MG, Duncton MA.
Abstract : The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.
|
Displacement of [3H]DPAT from 5HT1A receptor in Wistar rat hippocampus using 2 x 10' -7 by liquid scintillation counting
|
Rattus norvegicus
|
63.0
mg kg-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiarrhythmic, serotonin antagonist and antianxiety activities of novel substituted thiophene derivatives synthesized from 2-amino-4,5,6,7-tetrahydro-N-phenylbenzo[b]thiophene-3-carboxamide.
Year : 2010
Volume : 45
Issue : 12
First Page : 5935
Last Page : 5942
Authors : Amr Ael-G, Sherif MH, Assy MG, Al-Omar MA, Ragab I.
Abstract : A series of novel thiophene derivatives 3-17 were synthesized by initial reactions of 2-amino-4,5,6,7-tetrahydro-N-phenylbenzo[b]thiophene-3-carboxamide 1 and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitrile 7 with different organic reagents. The structures of newly synthesized compounds were confirmed by IR, 1H NMR, MS spectral data and elemental analysis. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds were screened for their antiarrhythmic, serotonin antagonist and antianexiety activities and they showed high activity compared with procaine amide, lidocaine, diazepam and buspirone as positive controls. The detailed synthesis, spectroscopic data, LD50 and pharmacological activities of the synthesized compounds were reported.
|
Displacement of [3H]DPAT from 5HT1A receptor in Wistar rat hippocampus using 2 x 10' -8 by liquid scintillation counting
|
Rattus norvegicus
|
87.0
mg kg-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiarrhythmic, serotonin antagonist and antianxiety activities of novel substituted thiophene derivatives synthesized from 2-amino-4,5,6,7-tetrahydro-N-phenylbenzo[b]thiophene-3-carboxamide.
Year : 2010
Volume : 45
Issue : 12
First Page : 5935
Last Page : 5942
Authors : Amr Ael-G, Sherif MH, Assy MG, Al-Omar MA, Ragab I.
Abstract : A series of novel thiophene derivatives 3-17 were synthesized by initial reactions of 2-amino-4,5,6,7-tetrahydro-N-phenylbenzo[b]thiophene-3-carboxamide 1 and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitrile 7 with different organic reagents. The structures of newly synthesized compounds were confirmed by IR, 1H NMR, MS spectral data and elemental analysis. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds were screened for their antiarrhythmic, serotonin antagonist and antianexiety activities and they showed high activity compared with procaine amide, lidocaine, diazepam and buspirone as positive controls. The detailed synthesis, spectroscopic data, LD50 and pharmacological activities of the synthesized compounds were reported.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT1A radioligand binding (ligand: [3H] 8-OH-DPAT)
|
None
|
16.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT1A radioligand binding (ligand: [3H] 8-OH-DPAT)
|
None
|
9.307
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
653.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
529.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
750.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
477.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
504.0
nM
|
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
212.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
323.0
nM
|
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
108.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
44.0
nM
|
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
15.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
TP_TRANSPORTER: increase in Calcein-AM intracellular accumulation (Calcein-AM: ? uM, Buspirone: 100 uM) in MDR1-expressing MDCKII cells
|
None
|
24.1
%
|
|
Journal : J. Pharmacol. Exp. Ther.
Title : Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
Year : 2002
Volume : 303
Issue : 1
First Page : 1029
Last Page : 1037
Authors : Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW.
Abstract : Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 microM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
33.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-5.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-13.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Displacement of [3H]5-carboxamidotryptamine to human 5HT1A expressed in HEK293 cells by filter binding assay
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.
Year : 2011
Volume : 54
Issue : 9
First Page : 3206
Last Page : 3221
Authors : Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB.
Abstract : The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor expressed in HEK293 cells after 1 hr
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety.
Year : 2013
Volume : 23
Issue : 15
First Page : 4419
Last Page : 4423
Authors : Waszkielewicz AM, Gunia A, Szkaradek N, Pytka K, Siwek A, Satała G, Bojarski AJ, Szneler E, Marona H.
Abstract : A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.
|
Displacement of [3H]-8-OH-DPAT from human recombinant 5-HT1A receptor expressed in HEK293 cell membrane after 1 hr by Microbeta scintillation counting analysis
|
Homo sapiens
|
22.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : SAR-studies on the importance of aromatic ring topologies in search for selective 5-HT(7) receptor ligands among phenylpiperazine hydantoin derivatives.
Year : 2014
Volume : 78
First Page : 324
Last Page : 339
Authors : Handzlik J, Bojarski AJ, Satała G, Kubacka M, Sadek B, Ashoor A, Siwek A, Więcek M, Kucwaj K, Filipek B, Kieć-Kononowicz K.
Abstract : The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8-353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40-3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.
|
Displacement of [3H]-8-OH-DPAT from 5-HT1AR in rat hippocampus
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT₁A receptor functional profile.
Year : 2015
Volume : 23
Issue : 1
First Page : 212
Last Page : 221
Authors : Partyka A, Chłoń-Rzepa G, Wasik A, Jastrzębska-Więsek M, Bucki A, Kołaczkowski M, Satała G, Bojarski AJ, Wesołowska A.
Abstract : Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4-14) and 7-tetrahydroisoquinolinyl-alkyl (15-17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.
|
Displacement of [3H]-8-OH-DPAT from human 5-HT1A receptor expressed in HEK293 cells
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Rational design in search for 5-phenylhydantoin selective 5-HT7R antagonists. Molecular modeling, synthesis and biological evaluation.
Year : 2016
Volume : 112
First Page : 258
Last Page : 269
Authors : Kucwaj-Brysz K, Warszycki D, Podlewska S, Witek J, Witek K, González Izquierdo A, Satała G, Loza MI, Lubelska A, Latacz G, Bojarski AJ, Castro M, Kieć-Kononowicz K, Handzlik J.
Abstract : A series of novel arylpiperazine 5-(4-fluorophenyl)-5-methylhydantoins with 2-hydroxypropyl linker (2-15) was synthesized and evaluated on their affinity towards serotonin 5-HT7 receptor (5-HT7R) in comparison to other closely related GPCRs: serotonin 5-HT1A, and dopamine D2 receptors. The functional activity studied through the measurement of 5-HT7R-mediated cyclic AMP production in Human Embryonic Kidney 293 cells (HEK293) stably expressing human 5-HT7 proved their antagonistic properties. The lead structure was also examined in the preliminary metabolic stability study using human liver microsomes (HMLs). The process of selection of candidates for synthesis was supported by a special molecular modeling workflow including combinatorial library generation, docking, and machine learning-based assessment. Additionally, in silico predictions of selectivity over 5-HT1AR and D2R, as well as functional activity were carried out. The newly synthesized compounds were proved to possess a potent affinity for 5-HT7R, similar to that of the lead structure of 5-(4-fluorophenyl)-3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-5-methylimidazolidine-2,4-dione (1). For several derivatives, significant selectivity both over 5-HT1AR and D2R was found.
|
Displacement of [3H]-8-OH-DPAT from 5HT1A receptor (unknown origin)
|
Homo sapiens
|
34.3
nM
|
|
Journal : ACS Med Chem Lett
Title : Pyrano[2,3,4-cd]indole as a Scaffold for Selective Nonbasic 5-HT6R Ligands.
Year : 2017
Volume : 8
Issue : 4
First Page : 390
Last Page : 394
Authors : Staroń J, Mordalski S, Warszycki D, Satała G, Hogendorf A, Bojarski AJ.
Abstract : In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through a tandem bioisostere generation/virtual screening protocol in search of 5-HT6R ligands. The discovered chemical scaffold resulted in the design of highly active basic and nonbasic 5-HT6R ligands (5-HT6R Ki = 1 nM for basic compound 6b and 5-HT6R Ki = 4 nM for its neutral analog 7b). Additionally, molecular modeling suggested that the hydroxyl group of nonbasic ligands 7a-7d forms hydrogen bonds with aspartic acid D3×32 or D7.36×35.
|
Displacement of [3H]methylspiperone from human D2 receptor expressed in HEK cells
|
Homo sapiens
|
484.0
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Binding affinity to 5-HT1A (unknown origin)
|
Homo sapiens
|
4.78
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Displacement of [3H]-8-OH-DPAT from human 5HT1AR expressed in HEK293 cell membranes after 1 hr by Microbeta scintillation counting method
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity.
Year : 2018
Volume : 147
First Page : 102
Last Page : 114
Authors : Kucwaj-Brysz K, Kurczab R, Jastrzębska-Więsek M, Żesławska E, Satała G, Nitek W, Partyka A, Siwek A, Jankowska A, Wesołowska A, Kieć-Kononowicz K, Handzlik J.
Abstract : This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,Ki ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di-phenyl ones.
|
Agonist activity at 5HT1A receptor (unknown origin)
|
Homo sapiens
|
8.9
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect.
Year : 2018
Volume : 145
First Page : 74
Last Page : 85
Authors : Xu M, Wang Y, Yang F, Wu C, Wang Z, Ye B, Jiang X, Zhao Q, Li J, Liu Y, Zhang J, Tian G, He Y, Shen J, Jiang H.
Abstract : In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine-induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development.
|
Displacement of [3H]-8-OH-DPAT from human 5-HT1A receptor expressed in HEK293 cell membranes after 1 hr by microbeta counting method
|
Homo sapiens
|
20.0
nM
|
|
Journal : MedChemComm
Title : The role of aryl-topology in balancing between selective and dual 5-HT<sub>7</sub>R/5-HT<sub>1A</sub> actions of 3,5-substituted hydantoins.
Year : 2018
Volume : 9
Issue : 6
First Page : 1033
Last Page : 1044
Authors : Kucwaj-Brysz K, Kurczab R, Żesławska E, Lubelska A, Marć MA, Latacz G, Satała G, Nitek W, Kieć-Kononowicz K, Handzlik J.
Abstract : In order to search for active and selective serotonin 5-HT<sub>7</sub>R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (<b>2</b>, KKB16) were performed. New derivatives (<b>4-18</b>) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione (<b>3</b>) was performed to support molecular modeling and SAR studies. The affinity for 5-HT<sub>7</sub>R, D<sub>2</sub>R and 5-HT<sub>1A</sub>R in radioligand binding assays for the entire series and ADME-Tox parameters <i>in vitro</i> for selected compounds (<b>7</b>, <b>10</b>, and <b>13</b>) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT<sub>7</sub>R agents (<i>K</i><sub>i</sub> ≤ 5 nM) with significant selectivity over 5-HT<sub>1A</sub>R and D<sub>2</sub>R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT<sub>7</sub>R/5-HT<sub>1A</sub>R action (<i>K</i><sub>i</sub>: 11 nM/19 nM).
|
Displacement of [3H]methylspiperone from human D2 receptor expressed in HEK-GIRK-M4 cell membrane by radioligand binding assay
|
Homo sapiens
|
484.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives.
Year : 2019
Volume : 29
Issue : 21
First Page : 126667
Last Page : 126667
Authors : Kułaga D, Jaśkowska J, Satała G.
Abstract : Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM - antagonist mode) and D2 (compound 15, Ki = 7 nM - antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.
|
Binding affinity to 5HT1A receptor (unknown origin)
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives.
Year : 2019
Volume : 29
Issue : 21
First Page : 126667
Last Page : 126667
Authors : Kułaga D, Jaśkowska J, Satała G.
Abstract : Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM - antagonist mode) and D2 (compound 15, Ki = 7 nM - antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.
|
Displacement of [3H]-8-OH-DPAT from human 5HT1A receptor expressed in CHO-K1 cell membranes incubated for 60 mins by microbeta scintillation counting analysis
|
Homo sapiens
|
21.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Displacement of [3H]-8-OH-DPAT from human 5-HT1A receptor expressed in HEK293 cells after 1 hr by microbeta plate reader analysis
|
Homo sapiens
|
34.3
nM
|
|
Journal : Eur J Med Chem
Title : Virtual screening-driven discovery of dual 5-HT<sub>6</sub>/5-HT<sub>2A</sub> receptor ligands with pro-cognitive properties.
Year : 2020
Volume : 185
First Page : 111857
Last Page : 111857
Authors : Staroń J, Kurczab R, Warszycki D, Satała G, Krawczyk M, Bugno R, Lenda T, Popik P, Hogendorf AS, Hogendorf A, Dubiel K, Matłoka M, Moszczyński-Pętkowski R, Pieczykolan J, Wieczorek M, Zajdel P, Bojarski AJ.
Abstract : A virtual screening campaign aimed at finding structurally new compounds active at 5-HT<sub>6</sub>R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT<sub>6</sub>R K<sub>i</sub> = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT<sub>6</sub>R K<sub>i</sub> = 25, 5-HT<sub>2A</sub>R K<sub>i</sub> = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.
|
Displacement of [3H]-8-OH-DPAT from human 5HT1A receptor expressed in HEK293 cells incubated for 1 hr by liquid scintillation counter method
|
Homo sapiens
|
32.36
nM
|
|
Displacement of [3H]-8-OH-DPAT from human 5HT1A receptor expressed in HEK293 cells incubated for 1 hr by liquid scintillation counter method
|
Homo sapiens
|
32.2
nM
|
|
Journal : Eur J Med Chem
Title : 2-Aminoimidazole-based antagonists of the 5-HT<sub>6</sub> receptor - A new concept in aminergic GPCR ligand design.
Year : 2019
Volume : 179
First Page : 1
Last Page : 15
Authors : Hogendorf AS, Hogendorf A, Kurczab R, Kalinowska-Tłuścik J, Popik P, Nikiforuk A, Krawczyk M, Satała G, Lenda T, Knutelska J, Bugno R, Staroń J, Pietruś W, Matłoka M, Dubiel K, Moszczyński-Pętkowski R, Pieczykolan J, Wieczorek M, Pilarski B, Zajdel P, Bojarski AJ.
Abstract : A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT<sub>6</sub>R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT<sub>6</sub>R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT<sub>6</sub>R and very high selectivity over 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>7</sub> and D<sub>2</sub> receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.
|
Displacement of [3H]-8-OH-DPAT from human 5-HT1A expressed in human HEK293 cells assessed as inhibitory constant incubated for 1 hr by radioligand binding assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and computer-aided SAR studies for derivatives of phenoxyalkyl-1,3,5-triazine as the new potent ligands for serotonin receptors 5-HT<sub>6</sub>.
Year : 2019
Volume : 178
First Page : 740
Last Page : 751
Authors : Ali W, Więcek M, Łażewska D, Kurczab R, Jastrzębska-Więsek M, Satała G, Kucwaj-Brysz K, Lubelska A, Głuch-Lutwin M, Mordyl B, Siwek A, Nasim MJ, Partyka A, Sudoł S, Latacz G, Wesołowska A, Kieć-Kononowicz K, Handzlik J.
Abstract : This research has provided the most active 5-HT<sub>6</sub>R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT<sub>6</sub>R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT<sub>6</sub>R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HT<sub>6</sub>R and selectivity, in respect to the 5-HT<sub>1A</sub>R, 5-HT<sub>2A</sub>R, 5-HT<sub>7</sub>R and dopamine D<sub>2</sub> receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT<sub>6</sub>R antagonist (K<sub>i</sub> = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT<sub>6</sub>R. Surprisingly, an introduction of SO<sub>2</sub> caused a drastic decrease of the 5-HT<sub>6</sub>R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro.
|
Displacement of [3H]-8-OH-DPAT from human recombinant 5-HT1A receptor expressed in HEK293 cells after 1 hr by microbeta scintillation counting method
|
Homo sapiens
|
32.2
nM
|
|
Journal : Eur J Med Chem
Title : Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers.
Year : 2019
Volume : 170
First Page : 261
Last Page : 275
Authors : Hogendorf AS, Hogendorf A, Popiołek-Barczyk K, Ciechanowska A, Mika J, Satała G, Walczak M, Latacz G, Handzlik J, Kieć-Kononowicz K, Ponimaskin E, Schade S, Zeug A, Bijata M, Kubicki M, Kurczab R, Lenda T, Staroń J, Bugno R, Duszyńska B, Pilarski B, Bojarski AJ.
Abstract : The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.
|
Displacement of [3H]-5-carboxamidotryptamine from human 5-HT7A receptor expressed in HEK293 cell membranes incubated for 90 mins by scintillation counting method
|
Homo sapiens
|
840.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.
Year : 2020
Volume : 28
Issue : 3
First Page : 115262
Last Page : 115262
Authors : Perry CK, Casey AB, Felsing DE, Vemula R, Zaka M, Herrington NB, Cui M, Kellogg GE, Canal CE, Booth RG.
Abstract : The serotonin 5-HT<sub>7</sub> G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT<sub>7</sub>. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT<sub>7</sub> GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT<sub>1A</sub> GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT<sub>7</sub> receptor for comparison with similar studies at the highly homologous 5-HT<sub>1A</sub> receptor. We report 35 new 5-SAT ligands, some with very high affinity (K<sub>i</sub> ≤ 1 nM) and stereoselectivity at 5-HT<sub>7</sub> + or 5-HT<sub>1A</sub> receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT<sub>7</sub>, and, several ligands with high selectivity (up to 40-fold) at the 5-HT<sub>1A</sub> receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT<sub>7</sub> over 5-HT<sub>1A</sub> receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT<sub>1A</sub> selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT<sub>7</sub> vs. 5-HT<sub>1A</sub> GPCRs, as may be required for successful clinical translation.
|
Displacement of [3H]-5-carboxamidotryptamine from human 5-HT1A receptor expressed in HEK293T cell membranes incubated for 90 mins by scintillation counting method
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.
Year : 2020
Volume : 28
Issue : 3
First Page : 115262
Last Page : 115262
Authors : Perry CK, Casey AB, Felsing DE, Vemula R, Zaka M, Herrington NB, Cui M, Kellogg GE, Canal CE, Booth RG.
Abstract : The serotonin 5-HT<sub>7</sub> G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT<sub>7</sub>. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT<sub>7</sub> GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT<sub>1A</sub> GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT<sub>7</sub> receptor for comparison with similar studies at the highly homologous 5-HT<sub>1A</sub> receptor. We report 35 new 5-SAT ligands, some with very high affinity (K<sub>i</sub> ≤ 1 nM) and stereoselectivity at 5-HT<sub>7</sub> + or 5-HT<sub>1A</sub> receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT<sub>7</sub>, and, several ligands with high selectivity (up to 40-fold) at the 5-HT<sub>1A</sub> receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT<sub>7</sub> over 5-HT<sub>1A</sub> receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT<sub>1A</sub> selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT<sub>7</sub> vs. 5-HT<sub>1A</sub> GPCRs, as may be required for successful clinical translation.
|
Displacement of [3H]8-OH-DPAT from human 5-HT1A receptor stably expressed in CHO-K1 cell membranes measured after 60 mins by Microbeta2 scintillation counting method
|
Homo sapiens
|
5.012
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10946
Last Page : 10971
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Latacz G,Przejczowska-Pomierny K,Wyska E,Wesołowska A,Pawłowski M,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
|
Biased agonist activity at human 5-HT1A receptor stably expressed in CHO-K1 cells assessed as increase in ERK1/2 phosphorylation after 15 mins by Alphalisa assay
|
Homo sapiens
|
15.14
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10946
Last Page : 10971
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Latacz G,Przejczowska-Pomierny K,Wyska E,Wesołowska A,Pawłowski M,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
|
Biased agonist activity at human 5-HT1A receptor stably expressed in CHO-K1 cells assessed as inhibition of forskolin-induced cAMP accumulation after 40 mins by LANCE Ultra cAMP kit-based TR-FRET assay
|
Homo sapiens
|
72.44
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10946
Last Page : 10971
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Latacz G,Przejczowska-Pomierny K,Wyska E,Wesołowska A,Pawłowski M,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
|
Biased agonist activity at Gal4-VP16 transcription factor linked human 5-HT1A receptor expressed in human U2OS cells assessed as induction of beta-arrestin2 recruitment measured after 5 hrs by Tango assay
|
Homo sapiens
|
186.21
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10946
Last Page : 10971
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Latacz G,Przejczowska-Pomierny K,Wyska E,Wesołowska A,Pawłowski M,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
|
Biased agonist activity at human 5-HT1A receptor stably expressed in CHO-K1 cells co-expressing Galpha16/GPCR assessed as increase in calcium mobilization measured for 30 secs in presence of coelenterazine by aequorin-reporter gene based luminescence assay
|
Homo sapiens
|
38.02
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10946
Last Page : 10971
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Latacz G,Przejczowska-Pomierny K,Wyska E,Wesołowska A,Pawłowski M,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
|
Displacement of [3H]8-OH-DPAT from recombinant human 5HT1A receptor stably expressed in CHO-K1 cell membranes measured after 60 mins by microbeta2 scintillation counting method
|
Homo sapiens
|
5.012
nM
|
|
Journal : J Med Chem
Title : Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.
Year : 2019
Volume : 62
Issue : 5.0
First Page : 2750
Last Page : 2771
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Pociecha K,Cios A,Wyska E,Wesołowska A,Pawłowski M,Varney MA,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
|
Biased agonist activity at human recombinant 5-HT1A receptor stably expressed in CHO-K1 cells assessed as increase in ERK1/2 phosphorylation levels incubated for 15 mins by Alphalisa assay
|
Homo sapiens
|
15.14
nM
|
|
Journal : J Med Chem
Title : Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.
Year : 2019
Volume : 62
Issue : 5.0
First Page : 2750
Last Page : 2771
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Pociecha K,Cios A,Wyska E,Wesołowska A,Pawłowski M,Varney MA,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
|
Biased agonist activity at human recombinant 5-HT1A receptor stably expressed in CHO-K1 cells assessed as inhibition of forskolin-induced cAMP accumulation after 40 mins by LANCE Ultra cAMP kit-based TR-FRET assay
|
Homo sapiens
|
72.44
nM
|
|
Journal : J Med Chem
Title : Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.
Year : 2019
Volume : 62
Issue : 5.0
First Page : 2750
Last Page : 2771
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Pociecha K,Cios A,Wyska E,Wesołowska A,Pawłowski M,Varney MA,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
|
Biased agonist activity at Gal4-VP16 transcription factor linked human 5-HT1A receptor expressed in human U2OS cells assessed as stimulation of beta-arrestin recruitment measured after 5 hrs by Tango assay
|
Homo sapiens
|
186.21
nM
|
|
Journal : J Med Chem
Title : Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.
Year : 2019
Volume : 62
Issue : 5.0
First Page : 2750
Last Page : 2771
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Pociecha K,Cios A,Wyska E,Wesołowska A,Pawłowski M,Varney MA,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
|
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor expressed in HEK293 cells measured after 1 hr by microbeta counting method
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel anilide and benzylamide derivatives of arylpiperazinylalkanoic acids as 5-HT/5-HT receptor antagonists and phosphodiesterase 4/7 inhibitors with procognitive and antidepressant activity.
Year : 2020
Volume : 201
First Page : 112437
Last Page : 112437
Authors : Jankowska A,Satała G,Kołaczkowski M,Bucki A,Głuch-Lutwin M,Świerczek A,Pociecha K,Partyka A,Jastrzębska-Więsek M,Lubelska A,Latacz G,Gawalska A,Bojarski AJ,Wyska E,Chłoń-Rzepa G
Abstract : A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT/5-HT receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT/5-HT receptor antagonist (5-HTK = 8 nM, K = 0.04 nM; 5-HTK = 451 nM, K = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC = 80.4 μM; PDE7A IC = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.
