|
Binding affinity towards human 5-hydroxytryptamine 1 receptor
|
None
|
830.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
In vitro binding affinity for 5-hydroxytryptamine 2 receptor
|
None
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacological evaluation of a diarylmethylene-piperidine derivative: a new potent atypical antipsychotic?
Year : 2001
Volume : 11
Issue : 10
First Page : 1313
Last Page : 1316
Authors : Talaga P, Matagne A, Klitgaard H.
Abstract : A new diaryl-methylene piperidine derivative, 2, displayed an atypical antipsychotic profile both in vitro and in vivo. The main pharmacological characteristics of this compound appears to reside in a more potent antagonism of the 5-HT2 serotonergic receptor than of the D2 dopaminergic receptor. This confirms that molecules displaying a D2/5-HT2 binding ratio < 1 possess clozapine-like antipsychotic activity.
|
Binding affinity towards human serotonin 5-hydroxytryptamine 2A receptor
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity for human 5-hydroxytryptamine 2A receptor
|
Homo sapiens
|
82.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Binding affinity towards human alpha-1 adrenergic receptor
|
None
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity towards human alpha-1 adrenergic receptor
|
None
|
4.5
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Binding affinity towards human alpha-2 adrenergic receptor
|
None
|
87.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity towards human Dopamine receptor D2
|
None
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity towards human D2 dopamine receptor.
|
None
|
69.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Binding affinity against dopamine receptor D1
|
None
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
In vitro binding affinity for Dopamine receptor D2
|
None
|
63.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacological evaluation of a diarylmethylene-piperidine derivative: a new potent atypical antipsychotic?
Year : 2001
Volume : 11
Issue : 10
First Page : 1313
Last Page : 1316
Authors : Talaga P, Matagne A, Klitgaard H.
Abstract : A new diaryl-methylene piperidine derivative, 2, displayed an atypical antipsychotic profile both in vitro and in vivo. The main pharmacological characteristics of this compound appears to reside in a more potent antagonism of the 5-HT2 serotonergic receptor than of the D2 dopaminergic receptor. This confirms that molecules displaying a D2/5-HT2 binding ratio < 1 possess clozapine-like antipsychotic activity.
|
Inhibition of spiropiperidone binding at dopamine receptor D2 of rat.
|
None
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.
Year : 2001
Volume : 44
Issue : 3
First Page : 372
Last Page : 389
Authors : Warawa EJ, Migler BM, Ohnmacht CJ, Needles AL, Gatos GC, McLaren FM, Nelson CL, Kirkland KM.
Abstract : A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.
|
Binding affinity towards human dopamine receptor D3
|
None
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Binding affinity towards human Dopamine receptor D3
|
None
|
650.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity towards human histamine H1 receptor
|
None
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective optimization of side activities: another way for drug discovery.
Year : 2004
Volume : 47
Issue : 6
First Page : 1303
Last Page : 1314
Authors : Wermuth CG.
|
Binding affinity towards human H1 receptor
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Binding affinity towards human M1 receptor.
|
None
|
56.0
nM
|
|
Journal : J. Med. Chem.
Title : Current and novel approaches to the drug treatment of schizophrenia.
Year : 2001
Volume : 44
Issue : 4
First Page : 477
Last Page : 501
Authors : Rowley M, Bristow LJ, Hutson PH.
|
Displacement of [3H]spiperone from human dopamine D3 receptor expressed in CHO cells
|
Homo sapiens
|
251.19
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor expressed in CHO cells
|
Homo sapiens
|
79.43
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]ketanserin from human 5HT2A receptor expressed in CHO cells
|
Homo sapiens
|
63.1
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]DOI from 5HT2B receptor expressed in CHO cells
|
Homo sapiens
|
251.19
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]LSD from human 5HT7 receptor expressed in CHO cells
|
Homo sapiens
|
63.1
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]pirenzepine from human M1 receptor expressed in CHO cells
|
Homo sapiens
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]4-DAMP from human M4 receptor expressed in CHO cells
|
Homo sapiens
|
125.89
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]prazosin from adrenergic alpha1 receptor in rat cerebral cortex
|
Rattus norvegicus
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]pyrilamine from histaminergic H1 receptor guinea pig cerebellum
|
Cavia porcellus
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs.
Year : 2007
Volume : 50
Issue : 21
First Page : 5103
Last Page : 5108
Authors : Lange JH, Reinders JH, Tolboom JT, Glennon JC, Coolen HK, Kruse CG.
Abstract : The receptor binding affinities of the three drug candidates 1 (SLV310), 2 (SLV313), and 3 (SLV314) were positioned against the results from nine (a)typical antipsychotic drugs. The receptor binding data from sixteen monoaminergic receptors served as the input in a principal component analysis (PCA). The PCA outcome revealed a unique binding profile of 1, 2, and 3 as compared with the reference compounds 4-8 and 10-12. The weight gain inducing antipsychotics 6-8 clustered in the PCA by scoring strongly negative for factor 1. The hyperprolactinaemia related antipsychotics 4, 5, 10, and 12 clustered by their negative scores for factor 2.
|
Displacement of [3H]mepyramine from H1R in rat brain
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase.
Year : 2007
Volume : 104
Issue : 9
First Page : 3456
Last Page : 3459
Authors : Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH.
Abstract : The atypical antipsychotic drugs (AAPDs) have markedly enhanced the treatment of schizophrenias but their use has been hindered by the major weight gain elicited by some AAPDs. We report that orexigenic AAPDs potently and selectively activate hypothalamic AMP-kinase, an action abolished in mice with deletion of histamine H1 receptors. These findings may afford a means of developing more effective therapeutic agents and provide insight into the hypothalamic regulation of food intake.
|
Binding affinity to human cloned muscarinic M1 receptor
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to human cloned dopamine D2 receptor
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to human cloned dopamine D3 receptor
|
Homo sapiens
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to human cloned histamine H1 receptor
|
Homo sapiens
|
8.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to human cloned 5HT1A receptor
|
Homo sapiens
|
230.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to human cloned 5HT2A receptor
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Binding affinity to rat NET
|
Rattus norvegicus
|
680.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
Year : 2008
Volume : 16
Issue : 15
First Page : 7291
Last Page : 7301
Authors : Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Kumar EV, Jackson T, Khan A, Roth BL.
Abstract : The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
|
Displacement of [3H]8OH-DPAT from 5HT1A in rat brain cerebral cortex after 15 mins by scintillation counting
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.
Year : 2011
Volume : 46
Issue : 9
First Page : 4474
Last Page : 4488
Authors : Słowiński T, Stefanowicz J, Dawidowski M, Kleps J, Czuczwar S, Andres-Mach M, Łuszczki JJ, Nowak G, Stachowicz K, Szewczyk B, Sławińska A, Mazurek AP, Mazurek A, Pluciński F, Wolska I, Herold F.
Abstract : The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.
|
Displacement of [3H]ketanserin from 5HT2A in rat brain cerebral cortex after 20 mins by scintillation counting
|
Rattus norvegicus
|
220.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.
Year : 2011
Volume : 46
Issue : 9
First Page : 4474
Last Page : 4488
Authors : Słowiński T, Stefanowicz J, Dawidowski M, Kleps J, Czuczwar S, Andres-Mach M, Łuszczki JJ, Nowak G, Stachowicz K, Szewczyk B, Sławińska A, Mazurek AP, Mazurek A, Pluciński F, Wolska I, Herold F.
Abstract : The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.
|
Displacement of [3H]spiperone from dopamine D2 receptor in rat striatum tissue after 20 mins by scintillation counting
|
Rattus norvegicus
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.
Year : 2011
Volume : 46
Issue : 9
First Page : 4474
Last Page : 4488
Authors : Słowiński T, Stefanowicz J, Dawidowski M, Kleps J, Czuczwar S, Andres-Mach M, Łuszczki JJ, Nowak G, Stachowicz K, Szewczyk B, Sławińska A, Mazurek AP, Mazurek A, Pluciński F, Wolska I, Herold F.
Abstract : The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
629.8
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: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
220.2
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-HT1A radioligand binding (ligand: [3H] 8-OH-DPAT)
|
None
|
815.1
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
|
117.8
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
33.6
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
86.2
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
34.9
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
24.5
nM
|
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
13.6
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
|
96.6
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
47.5
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
934.3
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
100.3
nM
|
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
45.8
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
420.8
nM
|
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
61.1
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
|
213.5
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
135.9
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
|
963.9
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 D1 radioligand binding (ligand: [3H] SCH-23390)
|
None
|
429.3
nM
|
|
DRUGMATRIX: Dopamine D1 radioligand binding (ligand: [3H] SCH-23390)
|
None
|
214.6
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
|
443.3
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
|
395.1
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: Histamine H1, Central radioligand binding (ligand: [3H] Pyrilamine)
|
None
|
39.6
nM
|
|
DRUGMATRIX: Histamine H1, Central radioligand binding (ligand: [3H] Pyrilamine)
|
None
|
4.599
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
|
Displacement of [3H]ketanserin from human recombinant 5HT2A receptor expressed in CHO cells after 60 mins by liquid scintillation counting
|
Homo sapiens
|
101.0
nM
|
|
Journal : J. Med. Chem.
Title : New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.
Year : 2012
Volume : 55
Issue : 4
First Page : 1572
Last Page : 1582
Authors : Liégeois JF, Deville M, Dilly S, Lamy C, Mangin F, Résimont M, Tarazi FI.
Abstract : A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.
|
Displacement of [3H]8-OH-DPAT from human recombinant 5HT1A receptor expressed in CHO cells after 60 mins by liquid scintillation counting
|
Homo sapiens
|
125.0
nM
|
|
Journal : J. Med. Chem.
Title : New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.
Year : 2012
Volume : 55
Issue : 4
First Page : 1572
Last Page : 1582
Authors : Liégeois JF, Deville M, Dilly S, Lamy C, Mangin F, Résimont M, Tarazi FI.
Abstract : A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.
|
Displacement of [3H]-MK-912 from human cloned adrenergic alpha2A receptor expressed in insect Sf9 cells at 10'-6 M after 60 mins by liquid scintillation counting
|
Homo sapiens
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.
Year : 2012
Volume : 55
Issue : 4
First Page : 1572
Last Page : 1582
Authors : Liégeois JF, Deville M, Dilly S, Lamy C, Mangin F, Résimont M, Tarazi FI.
Abstract : A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.
|
Binding affinity to adrenergic alpha1A receptor (unknown origin) by PDSP assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : MedChemComm
Title : The synthesis and receptor binding affinities of DDD-016, a novel, potential, atypical antipsychotic
Year : 2012
Volume : 3
Issue : 5
First Page : 580
Last Page : 583
Authors : Bandyopadhyaya A, Rajagopalan DR, Rath NP, Herrold A, Rajagopalan R, Napier TC, Tedford CE, Rajagopalan P
|
Binding affinity to adrenergic alpha1B receptor (unknown origin) by PDSP assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : MedChemComm
Title : The synthesis and receptor binding affinities of DDD-016, a novel, potential, atypical antipsychotic
Year : 2012
Volume : 3
Issue : 5
First Page : 580
Last Page : 583
Authors : Bandyopadhyaya A, Rajagopalan DR, Rath NP, Herrold A, Rajagopalan R, Napier TC, Tedford CE, Rajagopalan P
|
Binding affinity to adrenergic alpha2C receptor (unknown origin) by PDSP assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : MedChemComm
Title : The synthesis and receptor binding affinities of DDD-016, a novel, potential, atypical antipsychotic
Year : 2012
Volume : 3
Issue : 5
First Page : 580
Last Page : 583
Authors : Bandyopadhyaya A, Rajagopalan DR, Rath NP, Herrold A, Rajagopalan R, Napier TC, Tedford CE, Rajagopalan P
|
Binding affinity to H1 histamine receptor (unknown origin) by PDSP assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : MedChemComm
Title : The synthesis and receptor binding affinities of DDD-016, a novel, potential, atypical antipsychotic
Year : 2012
Volume : 3
Issue : 5
First Page : 580
Last Page : 583
Authors : Bandyopadhyaya A, Rajagopalan DR, Rath NP, Herrold A, Rajagopalan R, Napier TC, Tedford CE, Rajagopalan P
|
Binding Assay: Binding assay using 5-HT2A, Dopamine D2, SERT, αA1, 5-HT2C and H1 Receptors.
|
Homo sapiens
|
202.0
nM
|
|
Title : Methods and compositions for sleep disorders and other disorders
Year : 2013
|
Binding Assay: Binding assay using 5-HT2A, Dopamine D2, SERT, αA1, 5-HT2C and H1 Receptors.
|
Homo sapiens
|
10.0
nM
|
|
Title : Methods and compositions for sleep disorders and other disorders
Year : 2013
|
Binding Assay: Binding assay using 5-HT2A, Dopamine D2, SERT, αA1, 5-HT2C and H1 Receptors.
|
Homo sapiens
|
400.0
nM
|
|
Title : Methods and compositions for sleep disorders and other disorders
Year : 2013
|
Binding Assay: Binding assay using 5-HT2A, Dopamine D2, SERT, αA1, 5-HT2C and H1 Receptors.
|
Homo sapiens
|
20.0
nM
|
|
Title : Methods and compositions for sleep disorders and other disorders
Year : 2013
|
Displacement of [3H]-8-OH-DPAT from 5-HT1A receptor in human brain tissue incubated for 30 mins by scintillation counting analysis
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.
Year : 2019
Volume : 29
Issue : 21
First Page : 126679
Last Page : 126679
Authors : Żelaszczyk D, Jakubczyk M, Pytka K, Rapacz A, Walczak M, Janiszewska P, Pańczyk K, Żmudzki P, Słoczyńska K, Marona H, Waszkielewicz AM.
Abstract : Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT<sub>2</sub> receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT<sub>2A</sub>, 5-HT<sub>2B</sub> receptors and sodium channels.
|
Displacement of [3H]Ketanserin from 5-HT2A receptor in human brain tissue incubated for 60 mins by scintillation counting analysis
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.
Year : 2019
Volume : 29
Issue : 21
First Page : 126679
Last Page : 126679
Authors : Żelaszczyk D, Jakubczyk M, Pytka K, Rapacz A, Walczak M, Janiszewska P, Pańczyk K, Żmudzki P, Słoczyńska K, Marona H, Waszkielewicz AM.
Abstract : Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT<sub>2</sub> receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT<sub>2A</sub>, 5-HT<sub>2B</sub> receptors and sodium channels.
|
Binding affinity to H1 histamine receptor (unknown origin)
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Binding affinity to adrenergic alpha1 receptor (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Binding affinity to human dopamine D2 receptor
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.
Year : 2016
Volume : 24
Issue : 18.0
First Page : 3994
Last Page : 4007
Authors : Stefanowicz J,Słowiński T,Wróbel MZ,Herold F,Gomółka AE,Wesołowska A,Jastrzębska-Więsek M,Partyka A,Andres-Mach M,Czuczwar SJ,Łuszczki JJ,Zagaja M,Siwek A,Nowak G,Żołnierek M,Bączek T,Ulenberg S,Belka M,Turło J
Abstract : A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
|
Binding affinity to human 5HT1A receptor
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.
Year : 2016
Volume : 24
Issue : 18.0
First Page : 3994
Last Page : 4007
Authors : Stefanowicz J,Słowiński T,Wróbel MZ,Herold F,Gomółka AE,Wesołowska A,Jastrzębska-Więsek M,Partyka A,Andres-Mach M,Czuczwar SJ,Łuszczki JJ,Zagaja M,Siwek A,Nowak G,Żołnierek M,Bączek T,Ulenberg S,Belka M,Turło J
Abstract : A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
|
Binding affinity to human 5HT2A receptor
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.
Year : 2016
Volume : 24
Issue : 18.0
First Page : 3994
Last Page : 4007
Authors : Stefanowicz J,Słowiński T,Wróbel MZ,Herold F,Gomółka AE,Wesołowska A,Jastrzębska-Więsek M,Partyka A,Andres-Mach M,Czuczwar SJ,Łuszczki JJ,Zagaja M,Siwek A,Nowak G,Żołnierek M,Bączek T,Ulenberg S,Belka M,Turło J
Abstract : A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
|
Displacement of [3H]-ketanserin from human human 5-HT2A receptor transfected in CHO-K1 cells measured after 60 mins by scintillation counting method
|
Homo sapiens
|
120.23
nM
|
|
|
Displacement of [3H]-methylspiperone from human D2 receptor transfected in CHO-K1 cells measured after 60 mins by scintillation counting method
|
Homo sapiens
|
309.03
nM
|
|
|
Displacement of [3H]-scopolamine from human recombinant muscarinic M1 receptor expressed in human recombinant CHO-K1 cells at 1 uM incubated for 120 mins by solid scintillation counting method relative to control
|
Homo sapiens
|
88.0
%
|
|
|
Displacement of [3H]-pyrilamine from human recombinant histamine H1 receptor expressed in human recombinant CHO-K1 cells at 1 uM incubated for 60 mins by solid scintillation counting method relative to control
|
Homo sapiens
|
76.0
%
|
|
|
Displacement of [3H]-prazosin from rat cortex membrane alpha1 adrenergic receptor expressed in human recombinant CHO-K1 cells at 1 uM after 30 mins by solid scintillation counting method relative to control
|
Rattus norvegicus
|
75.0
%
|
|
