Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Abstract

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D₂-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D₂ antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D₃ and in particular D₄ receptors has been proposed. In vitro, all compounds, except the ‘typical’ antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D₂ receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D₂ receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D₂ affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D₄ than for D₂ receptors. For most other compounds, D₄ affinity was only slightly lower than their D₂ affinity. Seroquel was totally devoid of D₄ affinity. None of the compounds had nanomolar affinity for D₁ receptors; their affinity for D₃ receptors was usually slightly lower than for D₂ receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D₂ receptors. Risperidone and ORG-5222 had 5HT_2A versus D₂ potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D₂ receptors. No regional selectivity for D₂ receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D₂ receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic α₁ receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more α₁ than D₂ receptors. Clozapine showed predominant occupancy of H₁ receptors and occupied cholinergic receptors with equivalent potency to D₂ receptors. A stronger predominance of 5HT_2A versus D₂ receptor occupancy combined with a more gradual occupancy of D₂ receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D₂ receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D₂ occupancy and the avoidance of D₂ receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.