RISPERIDONE COMPARED WITH NEW AND REFERENCE ANTIPSYCHOTIC-DRUGS - IN-VITRO AND IN-VIVO RECEPTOR-BINDING

Risperidone and its active metabolite 9-OH-risperidone were compared t o reference antipsychotic drugs (haloperidol, pipamperone, fluspirilen e. clozapine, zotepine) and compounds under development (olanzapine, s eroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to ne urotransmitter receptors in brain tissue and on membranes of recombina nt cells expressing cloned human receptors and for in vivo occupancy o f neurotransmitter receptors in rat and guinea-pig brain following acu te treatment (2 h., s.c.). An ex vivo autoradiography technique was ap plied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT(2A) receptors and D- 2-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). D-2 antagonism is required for the treatment of positive symptoms. A contr ibution of the new dopamine receptor subtypes D-3 and in particular D- 4 receptors has been proposed. In vitro, all compounds, except the 'ty pical' antipsychotics haloperidol and fluspirilene, showed higher affi nity for 5HT(2A) than for D-2 receptors. Subnanomolar affinity for hum an 5HT(2A) receptors was observed for ORG-5222, sertindole, risperidon e, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperid ol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D-2 receptors, Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D-2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D-4 than for D-2 r eceptors. For most other compounds, D-4 affinity was only slightly low er than their D-2 affinity. Seroquel was totally devoid of D-4 affinit y. None of the compounds had nanomolar affinity for D-1, receptors: th eir affinity for D-3 receptors was usually slightly lower than for D-2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperid one. sertindole, olanzapine, zotepine and clozapine maintained a highe r potency for occupying 5HT(2A) than D-2 receptors. Risperidone and OR G-5222 had 5HT(2A) versus D-2 potency ratio of about 20. Highest poten cy for 5HT(2A) receptor occupancy was observed for ORG-5222 followed b y risperidone and olanzapine. Ziprasidone exclusively occupied 5HT(2A) receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D-2 receptors. No regional selectivi ty for D-2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuo us because of its more gradual occupancy of D-2 receptors; none of the other compounds showed this property. The various compounds also disp layed high to moderate occupancy of adrenergic alpha(1) receptors, exc ept fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and se rtindole occupied even more alpha(1) than D-2 receptors. Clozapine sho wed predominant occupancy of H-1 receptors and occupied cholinergic re ceptors with equivalent potency to D-2 receptors. A stronger predomina nce of 5HT(2A) versus D-2 receptor occupancy combined with a more grad ual occupancy of D-2 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 be neficial action of risperidone on the negative symptoms of schizophren ia, whereas maintenance of a moderate occupancy of D-2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combi ned 5HT(2A) and D-2 occupancy and the avoidance of D-2 receptor overbl ockade are believed to reduce the risk for extrapyramidal symptoms.