title: Receptor profile of P88-8991 and P95-12113, metabolites of the novel antipsychotic iloperidone.
abstract: Iloperidone is a novel atypical antipsychotic compound currently under clinical development for the treatment of psychotic disorders. In radioligand binding studies, iloperidone binds with high affinity to serotonin (5-HT) 5-HT2A and noradrenaline alpha1 and alpha2C receptors [Neuropsychopharmacology (2001) 25, 904-914]. The human metabolism of iloperidone generates two major metabolites, P88-8991 and P95-12113. The aim of this study was to compare the receptor affinity profile of P88-8991 and P95-12113 with that of the parent compound. The receptor affinity profile of P88-8991 is comparable to that of iloperidone. This metabolite binds to the following monoamine receptors (pKi values in nM): serotonin 5-HT2A receptors (9.56), adrenergic alpha1 (8.08) and alpha2C (7.79) receptors, and D2A receptors (7.80). Lower affinity is seen for other dopamine, serotonin, alpha2-adrenergic and histamine H1 receptors. In contrast, P95-12113 shows affinity for 5-HT2A receptors (pKi 8.15; which is 60-fold lower than that of iloperidone), adrenergic alpha1 (7.67), alpha2C (7.32) and alpha2B (7.08) receptors. Given this affinity profile, and the observation that P95-12113 does not readily cross the blood-brain barrier, it is unlikely that this metabolite contributes to the therapeutic effect of iloperidone in patients with schizophrenia. However, the comparable receptor binding profile of P88-8991 indicates that it is likely to contribute to the clinical profile of iloperidone.
authors: Novartis Pharma AG, Research Nervous System, Basel, Switzerland.
authors: Natarajan
authors: N
authors: Subramanian
authors: Hans O
authors: HO
authors: Kalkman
mesh_terms: D016475:3T3 Cells; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D010880:Piperidines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C081732:iloperidone