Receptor profile of P88-8991 and P95-12113, metabolites of the novel antipsychotic iloperidone.
Prog Neuropsychopharmacol Biol Psychiatry
; 26(3): 553-60, 2002 Apr.
Article
em En
| MEDLINE
| ID: mdl-11999907
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.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Antipsicóticos
/
Receptores de Serotonina
/
Receptores Dopaminérgicos
/
Isoxazóis
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article