RISPERIDONE - A NOVEL ANTIPSYCHOTIC WITH BALANCED SEROTONIN-DOPAMINE ANTAGONISM, RECEPTOR OCCUPANCY PROFILE, AND PHARMACOLOGICAL ACTIVITY

The interaction of risperidone, 9-hydroxyrisperidone (the principal ac tive metabolite), and clozapine with neurotransmitter receptors was in vestigated in vitro using animal brain tissue homogenates and cloned h uman receptors expressed in cells and ex vivo using quantitative recep tor autoradiography in rat and guinea pig brain sections. In vitro, ri speridone and 9-hydroxyrisperidone had similar binding profiles, and t heir highest affinity was for 5-HT2A receptors (cloned human, K(i) 0.4 nM); affinities for other 5-HT-receptor subtypes were at least 100 ti mes lower. Risperidone bound to 5-HT2A receptors with 20 times greater affinity than clozapine and 170 times greater affinity than haloperid ol. Clozapine primarily bound to histamine H-1 receptors and haloperid ol to dopamine D2 receptors. The binding affinity of risperidone and 9 -hydroxyrisperidone for the D2 family of receptors (D2L, D2S, D3, D4) was one order of magnitude lower than their affinity for 5-HT2A recept ors. Risperidone bound to D2 and D3 receptors with 50 and 20 times gre ater affinity than clozapine and was only 2 to 3 times less potent tha n haloperidol. All compounds bound with similar affinities to D4 recep tors (K(i) 5-9 nM), and their affinities for D1 receptors were 100 tim es lower than for D4 receptors. The ex vivo receptor occupancy profile of the compounds matched the in vitro receptor binding profile. A con spicuous property of risperidone, not seen for the other compounds, wa s the shallow occupancy curve at D2 receptors in the striatum and meso limbic brain area. Moreover, it was observed that antagonism of strong D2-receptor stimulation by apomorphine in rats was achieved at less t han 50% D2 occupancy by the antipsychotics. A balance of full 5-HT2A-r eceptor occupancy and partial D2-receptor occupancy probably underlies the beneficial therapeutic action of risperidone on both positive and negative symptoms of schizophrenia and the low tendency to cause extr apyramidal side effects.