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 alpha(1) and alpha(2C) 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 (pK(i) values in nM): scrotonin 5-HT2A receptors (9.56), adrenergic alpha(1) (8.08) and alpha(2C) (7.79) receptors, and D-2A receptors (7.80). Lower affinity is seen for other dopamine, scrotonin, alpha(2)-adrenergic and histamine H-1 receptors. In contrast, P95-12113 shows affinity for 5-HT2A receptors (pK(1) 8.15; which is 60-fold lower than that of iloperidone), adrenergic alpha(1) (7.67), alpha(2C) (7.32) and alpha(2B) (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. (C) 2001 Elsevier Science Inc. All rights reserved.