Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity
Leysen, J.E.; Janssen, P.M.; Megens, A.A.; Schotte, A.
Journal of Clinical Psychiatry 55(Suppl): 5-12
1994
ISSN/ISBN: 0160-6689 PMID: 7520908 Document Number: 3549
The interaction of risperidone, 9-hydroxyrisperidone (the principal active metabolite), and clozapine with neurotransmitter receptors was investigated in vitro using animal brain tissue homogenates and cloned human receptors expressed in cells and ex vivo using quantitative receptor autoradiography in rat and guinea pig brain sections. In vitro, risperidone and 9-hydroxyrisperidone had similar binding profiles, and their highest affinity was for 5-HT-2A receptors (cloned human, K-i 0.4 nM); affinities for other 5-HT-receptor subtypes were at least 100 times lower. Risperidone bound to 5-HT-2A receptors with 20 times greater affinity than clozapine and 170 times greater affinity than haloperidol. Clozapine primarily bound to histamine H-1 receptors and haloperidol to dopamine D-2 receptors. The binding affinity of risperidone and 9-hydroxyrisperidone for the D-2 family of receptors (D-2L, D-2S, D-3, D-4) was one order of magnitude lower than their affinity for 5-HT-2A receptors. Risperidone bound to D-2 and D-3 receptors with 50 and 20 times greater affinity than clozapine and was only 2 to 3 times less potent than haloperidol. All compounds bound with similar affinities to D-4 receptors (K-i 5-9 nM), and their affinities for D-1 receptors were 100 times lower than for D-4 receptors. The ex vivo receptor occupancy profile of the compounds matched the in vitro receptor binding profile. A conspicuous property of risperidone, not seen for the other compounds, was the shallow occupancy curve at D-2 receptors in the striatum and mesolimbic brain area. Moreover, it was observed that antagonism of strong D-2-receptor stimulation by apomorphine in rats was achieved at less than 50% D-2 occupancy by the antipsychotics. A balance of full 5-HT-2A-receptor occupancy and partial D-2-receptor occupancy probably underlies the beneficial therapeutic action of risperidone on both positive and negative symptoms of schizophrenia and the low tendency to cause extrapyramidal side effects.
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