title: Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.
abstract: Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi<or=5) for muscarinic receptors and was the only agent with affinity for H2 receptors. Relative to its D2 receptor affinity, asenapine had a higher affinity for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6, alpha2B and D3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2 (9.1), D3 (9.1), alpha2A (7.3), alpha2B (8.3), alpha2C (6.8) and H1 (8.4) receptors. These functional effects differed from those of risperidone (pKB<5 for 5-HT6) and olanzapine (pKB<5 for 5-HT1A and alpha2). Our results indicate that asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of antipsychotic drugs.
authors.affiliation: Schering-Plough, Newhouse, Lanarkshire, UK. mohammed.shahid@spcorp.com
authors.forename: M
authors.initials: M
authors.lastname: Shahid
authors.forename: G B
authors.initials: GB
authors.lastname: Walker
authors.forename: S H
authors.initials: SH
authors.lastname: Zorn
authors.forename: E H F
authors.initials: EH
authors.lastname: Wong
mesh_terms: D001569:Benzodiazepines / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy; D002986:Clinical Trials as Topic; D003001:Cloning, Molecular; D003024:Clozapine / Q000494:pharmacology; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006636:Histamine Release / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D000077152:Olanzapine; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D011941:Receptors, Adrenergic / Q000187:drug effects* / Q000235:genetics; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy; D013379:Substrate Specificity
chemical_list: D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D011619:Psychotropic Drugs; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D001569:Benzodiazepines; D003024:Clozapine; C522667:asenapine; D000077152:Olanzapine