Binding affinity towards human 5-hydroxytryptamine 1 receptor
|
None
|
37.0
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 serotonin 5-hydroxytryptamine 2A receptor
|
None
|
0.3
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
|
0.25
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]-ketanserin from rat brain 5-hydroxytryptamine 2A receptor
|
Rattus norvegicus
|
0.4169
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Relative binding affinity for D2 receptor and 5-hydroxytryptamine 2A receptor, ratio of Ki
|
Rattus norvegicus
|
0.42
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Binding affinity towards human serotonin 5-hydroxytryptamine 2C receptor
|
None
|
13.0
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 5-hydroxytryptamine 2C receptor
|
None
|
0.55
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]prazosin from Alpha-1 adrenergic receptor in rat brain
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Displacement of [3H]prazosin from rat brain Alpha-1 adrenergic receptor
|
Rattus norvegicus
|
10.47
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Binding affinity towards human alpha-1 adrenergic receptor
|
None
|
12.0
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
|
1.9
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
|
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.
Binding affinity towards human alpha-2 adrenergic receptor
|
None
|
390.0
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-4.2 receptor
|
None
|
39.0
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
|
9.7
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
|
2.8
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
|
9.5
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 Dopamine receptor D1
|
None
|
330.0
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 D4
|
None
|
39.0
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]NPA from rat brain Dopamine receptor D2
|
Rattus norvegicus
|
4.786
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Binding affinity towards human dopamine receptor D3
|
None
|
10.0
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]NPA from rat brain Dopamine receptor D2
|
Rattus norvegicus
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents.
Year : 1996
Volume : 39
Issue : 1
First Page : 143
Last Page : 148
Authors : Howard HR, Lowe JA, Seeger TF, Seymour PA, Zorn SH, Maloney PR, Ewing FE, Newman ME, Schmidt AW, Furman JS, Robinson GL, Jackson E, Johnson C, Morrone J.
Abstract : A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
Binding affinity towards human Dopamine receptor D3
|
None
|
7.5
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
|
510.0
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 histamine H1 receptor
|
None
|
5.3
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.
K+ channel blocking activity in human embryonic kidney cells expressing HERG Kv11.1
|
Homo sapiens
|
152.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
Year : 2002
Volume : 45
Issue : 18
First Page : 3844
Last Page : 3853
Authors : Cavalli A, Poluzzi E, De Ponti F, Recanatini M.
Abstract : In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.
Inhibitory concentration against potassium channel HERG
|
None
|
120.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2886
Last Page : 2890
Authors : Tobita M, Nishikawa T, Nagashima R.
Abstract : HERG attracts attention as a risk factor for arrhythmia, which might trigger torsade de pointes. A highly accurate classifier of chemical compounds for inhibition of the HERG potassium channel is constructed using support vector machine. For two test sets, our discriminant models achieved 90% and 95% accuracy, respectively. The classifier is even applied for the prediction of cardio vascular adverse effects to achieve about 70% accuracy. While modest inhibitors are partly characterized by properties linked to global structure of a molecule including hydrophobicity and diameter, strong inhibitors are exclusively characterized by properties linked to substructures of a molecule.
Inhibition of partially open human voltage-gated potassium channel subunit Kv11.1 (ERG K+ channel)
|
Homo sapiens
|
151.36
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A two-state homology model of the hERG K+ channel: application to ligand binding.
Year : 2005
Volume : 15
Issue : 6
First Page : 1737
Last Page : 1741
Authors : Rajamani R, Tounge BA, Li J, Reynolds CH.
Abstract : Homology models based on available K+ channel structures have been used to construct a multiple state representation of the hERG cardiac K+ channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56 kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability.
Inhibitory concentration against dopamine receptor D2
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
Inhibitory concentration against alpha adrenergic receptor
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
Inhibitory concentration against 5-hydroxytryptamine 2 receptor
|
Homo sapiens
|
0.42
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
Displacement of [3H]spiperone from human dopamine D2 receptor short form expressed in CHO cells
|
Homo sapiens
|
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]spiperone from human dopamine D3 receptor expressed in CHO cells
|
Homo sapiens
|
6.31
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]spiperone from human dopamine D4.4 receptor expressed in CHO cells
|
Homo sapiens
|
50.12
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
|
1.585
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
|
0.631
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 5HT2B receptor expressed in CHO cells
|
Homo sapiens
|
1.585
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]mesulergine from 5HT2C receptor expressed in CHO cells
|
Homo sapiens
|
1.259
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 5HT6 receptor expressed in HEK293 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]LSD from human 5HT7 receptor expressed in CHO cells
|
Homo sapiens
|
5.012
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]BLR-43694 from human 5HT3 receptor expressed in HEK293 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]paraxetine from human 5HT transporter expressed in HEK293 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]prazosin from adrenergic alpha1 receptor in rat cerebral cortex
|
Rattus norvegicus
|
7.943
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]RX 821002 from adrenergic alpha-2 receptor in rat cerebral cortex
|
Rattus norvegicus
|
501.19
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]pyrilamine from histaminergic H1 receptor guinea pig cerebellum
|
Cavia porcellus
|
15.85
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]spiperone from human D2L receptor expressed in CHO cells
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Aminoindanes as novel motif with potential atypical antipsychotic properties.
Year : 2008
Volume : 18
Issue : 2
First Page : 489
Last Page : 493
Authors : Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS.
Abstract : As part of an on-going effort to investigate the chemical space requirements for D(2)/5-HT(2A) receptor antagonists as atypical antipsychotics, new 1-aminoindanes were synthesized. The replacement of the heterocycle (oxindole) in ziprasidone with a carbocycle (indane) was well tolerated and was found to retain binding affinities for dopamine D(2), serotonin 5-HT(2A), and serotonin 5-HT(1A). Such compounds hold promise as a new chemical motif with atypical antipsychotic properties for the treatment of schizophrenia and related disorders.
Displacement of [3H]ketanserin from human 5HT2A receptor expressed in Swiss 3T3 cells
|
Homo sapiens
|
0.08
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Aminoindanes as novel motif with potential atypical antipsychotic properties.
Year : 2008
Volume : 18
Issue : 2
First Page : 489
Last Page : 493
Authors : Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS.
Abstract : As part of an on-going effort to investigate the chemical space requirements for D(2)/5-HT(2A) receptor antagonists as atypical antipsychotics, new 1-aminoindanes were synthesized. The replacement of the heterocycle (oxindole) in ziprasidone with a carbocycle (indane) was well tolerated and was found to retain binding affinities for dopamine D(2), serotonin 5-HT(2A), and serotonin 5-HT(1A). Such compounds hold promise as a new chemical motif with atypical antipsychotic properties for the treatment of schizophrenia and related disorders.
Displacement of [3H]8OHDPAT from human 5HT1A receptor
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Aminoindanes as novel motif with potential atypical antipsychotic properties.
Year : 2008
Volume : 18
Issue : 2
First Page : 489
Last Page : 493
Authors : Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS.
Abstract : As part of an on-going effort to investigate the chemical space requirements for D(2)/5-HT(2A) receptor antagonists as atypical antipsychotics, new 1-aminoindanes were synthesized. The replacement of the heterocycle (oxindole) in ziprasidone with a carbocycle (indane) was well tolerated and was found to retain binding affinities for dopamine D(2), serotonin 5-HT(2A), and serotonin 5-HT(1A). Such compounds hold promise as a new chemical motif with atypical antipsychotic properties for the treatment of schizophrenia and related disorders.
Displacement of [3H]prazosin from rat adrenergic alpha1A receptor expressed in fibroblast cells
|
Rattus norvegicus
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Aminoindanes as novel motif with potential atypical antipsychotic properties.
Year : 2008
Volume : 18
Issue : 2
First Page : 489
Last Page : 493
Authors : Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS.
Abstract : As part of an on-going effort to investigate the chemical space requirements for D(2)/5-HT(2A) receptor antagonists as atypical antipsychotics, new 1-aminoindanes were synthesized. The replacement of the heterocycle (oxindole) in ziprasidone with a carbocycle (indane) was well tolerated and was found to retain binding affinities for dopamine D(2), serotonin 5-HT(2A), and serotonin 5-HT(1A). Such compounds hold promise as a new chemical motif with atypical antipsychotic properties for the treatment of schizophrenia and related disorders.
Displacement of [3H]mepyramine from H1R in rat brain
|
Rattus norvegicus
|
150.0
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 5HT6 receptor
|
Homo sapiens
|
76.0
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 D1 receptor
|
Homo sapiens
|
130.0
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
|
3.1
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
|
7.2
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 D4 receptor
|
Homo sapiens
|
32.0
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 5HT2C receptor
|
Homo sapiens
|
0.72
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
|
47.0
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 5HT1A receptor
|
Homo sapiens
|
2.5
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
|
0.39
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
|
48.0
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 SERT
|
Homo sapiens
|
53.0
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.
Inhibition of human ERG channel
|
Homo sapiens
|
125.0
nM
|
|
Inhibition of human ERG channel
|
Homo sapiens
|
125.0
nM
|
|
Journal : J. Med. Chem.
Title : Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
Year : 2009
Volume : 52
Issue : 14
First Page : 4266
Last Page : 4276
Authors : Zachariae U, Giordanetto F, Leach AG.
Abstract : The cardiac hERG K(+) channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
Inhibition of human ERG expressed in CHO cells by whole cell patch clamp technique
|
Homo sapiens
|
120.23
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Support vector machines classification of hERG liabilities based on atom types.
Year : 2008
Volume : 16
Issue : 11
First Page : 6252
Last Page : 6260
Authors : Jia L, Sun H.
Abstract : Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed.
Inhibition of human ERG in MCF7 cells
|
Homo sapiens
|
151.36
nM
|
|
Journal : Eur. J. Med. Chem.
Title : GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers.
Year : 2009
Volume : 44
Issue : 5
First Page : 1926
Last Page : 1932
Authors : Ermondi G, Visentin S, Caron G.
Abstract : The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844-53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K(+) channel blocking activity. As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
-5.07
%
|
|
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.
Inhibition of human ERG
|
Homo sapiens
|
125.89
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.
Year : 2011
Volume : 46
Issue : 2
First Page : 618
Last Page : 630
Authors : Sinha N, Sen S.
Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.
Displacement of [3H]mesulergine from human 5HT2C receptor in human tsA201 cells
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands.
Year : 2010
Volume : 20
Issue : 18
First Page : 5431
Last Page : 5433
Authors : Krogsgaard-Larsen N, Jensen AA, Kehler J.
Abstract : Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C-H insertion of a carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-ligands.
Displacement of [3H]5-LSD from human 5HT6 receptor expressed in human HeLa cells
|
Homo sapiens
|
61.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands.
Year : 2010
Volume : 20
Issue : 18
First Page : 5431
Last Page : 5433
Authors : Krogsgaard-Larsen N, Jensen AA, Kehler J.
Abstract : Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C-H insertion of a carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-ligands.
Inhibition of norA-mediated ethidium bromide efflux in Staphylococcus aureus SA-1199B harboring grlA A116E mutant at 50 uM after 5 mins by fluorometric analysis
|
Staphylococcus aureus
|
86.6
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA.
Year : 2012
Volume : 3
Issue : 3
First Page : 248
Last Page : 251
Authors : Brincat JP, Broccatelli F, Sabatini S, Frosini M, Neri A, Kaatz GW, Cruciani G, Carosati E.
Abstract : Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.
Inhibition of human recombinant MDR1 expressed in mouse L5178Y cells assessed as inhibition of rhodamine-123 efflux at 10'-4 M preincubated for 10 mins measured after 20 mins by FACS analysis
|
Homo sapiens
|
19.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA.
Year : 2012
Volume : 3
Issue : 3
First Page : 248
Last Page : 251
Authors : Brincat JP, Broccatelli F, Sabatini S, Frosini M, Neri A, Kaatz GW, Cruciani G, Carosati E.
Abstract : Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.
Displacement of [3H]methylspiperone from human low affinity Dopamine D2S receptor by competition binding assay
|
Homo sapiens
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.
Year : 2012
Volume : 55
Issue : 22
First Page : 9735
Last Page : 9750
Authors : Mattsson C, Andreasson T, Waters N, Sonesson C.
Abstract : A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.
Binding affinity to adrenergic alpha1 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to 5HT7 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to 5HT6 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
61.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to 5HT2C receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to dopamine D3 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to 5HT2A receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding affinity to dopamine D2 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Binding Assay: Binding assay using 5-HT2A, Dopamine D2, SERT, αA1, 5-HT2C and H1 Receptors.
|
Homo sapiens
|
0.28
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
|
112.0
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
|
15.0
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
|
5.0
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
|
6.0
nM
|
|
Title : Methods and compositions for sleep disorders and other disorders
Year : 2013
Displacement of [3H]-Raclopride from D2L receptor (unknown origin)
|
Homo sapiens
|
2.1
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]-ketanserin from human 5-HT2AR expressed in CHO-K1 cell membranes after 1.5 hrs by microbeta counting method
|
Homo sapiens
|
1.7
nM
|
|
Journal : Eur J Med Chem
Title : Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.
Year : 2018
Volume : 145
First Page : 790
Last Page : 804
Authors : Zajdel P, Kos T, Marciniec K, Satała G, Canale V, Kamiński K, Hołuj M, Lenda T, Koralewski R, Bednarski M, Nowiński L, Wójcikowski J, Daniel WA, Nikiforuk A, Nalepa I, Chmielarz P, Kuśmierczyk J, Bojarski AJ, Popik P.
Abstract : Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Displacement of [3H]-LSD from human 5-HT6R expressed in HEK293 cell membranes after 1 hr at 37 degC by microbeta counting method
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.
Year : 2018
Volume : 145
First Page : 790
Last Page : 804
Authors : Zajdel P, Kos T, Marciniec K, Satała G, Canale V, Kamiński K, Hołuj M, Lenda T, Koralewski R, Bednarski M, Nowiński L, Wójcikowski J, Daniel WA, Nikiforuk A, Nalepa I, Chmielarz P, Kuśmierczyk J, Bojarski AJ, Popik P.
Abstract : Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Displacement of [3H]-8-OH-DPAT from human 5-HT1AR expressed in HEK293 cell membranes after 1 hr by microbeta counting method
|
Homo sapiens
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.
Year : 2018
Volume : 145
First Page : 790
Last Page : 804
Authors : Zajdel P, Kos T, Marciniec K, Satała G, Canale V, Kamiński K, Hołuj M, Lenda T, Koralewski R, Bednarski M, Nowiński L, Wójcikowski J, Daniel WA, Nikiforuk A, Nalepa I, Chmielarz P, Kuśmierczyk J, Bojarski AJ, Popik P.
Abstract : Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Displacement of [3H]-5-CT from human 5-HT7R expressed in HEK293 cell membranes after 1 hr at 37 degC by microbeta counting method
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.
Year : 2018
Volume : 145
First Page : 790
Last Page : 804
Authors : Zajdel P, Kos T, Marciniec K, Satała G, Canale V, Kamiński K, Hołuj M, Lenda T, Koralewski R, Bednarski M, Nowiński L, Wójcikowski J, Daniel WA, Nikiforuk A, Nalepa I, Chmielarz P, Kuśmierczyk J, Bojarski AJ, Popik P.
Abstract : Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Displacement of [3H]-raclopride from human D2LR expressed in HEK293 cell membranes after 1 hr at 37 degC by microbeta counting method
|
Homo sapiens
|
0.8
nM
|
|
Journal : Eur J Med Chem
Title : Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.
Year : 2018
Volume : 145
First Page : 790
Last Page : 804
Authors : Zajdel P, Kos T, Marciniec K, Satała G, Canale V, Kamiński K, Hołuj M, Lenda T, Koralewski R, Bednarski M, Nowiński L, Wójcikowski J, Daniel WA, Nikiforuk A, Nalepa I, Chmielarz P, Kuśmierczyk J, Bojarski AJ, Popik P.
Abstract : Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Displacement of [3H]-raclopride from human D2R expressed in HEK293 cells after 1 hr by microbeta plate reader analysis
|
Homo sapiens
|
2.1
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]-methylspiperone from human D2 long receptor expressed in HEK293 cells measured after 1 hr by liquid scintillation counter method
|
Homo sapiens
|
0.8511
nM
|
|
Displacement of [3H]-methylspiperone from human D2 long receptor expressed in HEK293 cells measured after 1 hr by liquid scintillation counter method
|
Homo sapiens
|
0.9
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] raclopride from human recombinant D2L receptor expressed in HEK293 cells measured after 1 hr by microbeta scintillation counting method
|
Homo sapiens
|
0.9
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.
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.21
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
Binding affinity to H1 histamine receptor (unknown origin)
|
Homo sapiens
|
50.0
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
|
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.