BINDING OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC AGENTS TO 5-HYDROXYTRYPTAMINE-6 AND 5-HYDROXYTRYPTAMINE-7 RECEPTORS

The authors examined the affinities of 36 typical and atypical antipsy chotic agents for the cloned rat 5-hydroxytryptamine-6 (5-HT6) and rat 5-hydroxytryptamine-7 (5-HT7) receptors in transiently expressed COS- 7 cells (5-HT7) or stably transfected HEK-293 cells (5-HT6 receptors). Clozapine and several related atypical antipsychotic agents (rilapine , olanzepine, tiospirone, fluperlapine, clorotepine and zotepine) had high affinities for the newly discovered 5-HT6 receptor (K(i)s < 20 nM ). The 5-HT7 receptor bound clozapine, rilapine, fluperlapine, clorote pine, zotepine and risperidone but not tiospirone and olanzepine, with affinities less than 15 nM. In addition, several typical antipsychoti c agents (chlorprothixene, chlorpromazine, clothiapine and fluphenazin e) had high affinities for both the 5-HT6 and 5-HT7 receptors. Pimozid e, a diphenylbutylpiperidine, had the highest affinity of all the typi cal antipsychotic agents tested for the 5-HT7 receptor (K-i = 0.5 nM). Three putative atypical antipsychotic agents melperone, amperozide an d MDL 100907 did not bind with high affinities to either the 5-HT6 or 5-HT7 receptors (K(i)s > 50 nM). Several dopamine-selective antipsycho tic agents (raclopride, rimcazole and penfluridol) had essentially no affinity for either the 5HT(6) or 5-HT7 receptors (K-i values > 5000 n M). Although 5-HT6 or 5-HT7 receptor affinity alone does not predict w hether or not a drug will have atypical antipsychotic activity, the re latively high affinity of the 5-HT6 receptor for several clozapine-rel ated compounds, in combination with the enrichment of 5-HT6 messenger RNA in the striatum, suggests that the ability of at least some atypic al antipsychotic drugs to interact with 5-HT6 receptors may contribute to their lack of extrapyramidal side effects.