Binding of typical and atypical antipsychotic agents to 5- hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors

B. L. Roth*, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

674 Scopus citations


The authors examined the affinities of 36 typical and atypical antipsychotic 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, clorotepine, zotepine and risperidone but not tiospirone and olanzepine, with affinities less than 15 nM. In addition, several typical antipsychotic agents (chlorprothixene, chlorpromazine, clothiapine and fluphenazine) had high affinities for both the 5-HT6 and 5-HT7 receptors. Pimozide, a diphenylbutylpiperidine, had the highest affinity of all the typical antipsychotic agents tested for the 5- HT7 receptor (K(i) = 0.5 nM). Three putative atypical antipsychotic agents melperone, amperozide and 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 antipsychotic agents (raclopride, rimcazole and penfluridol) had essentially no affinity for either the 5-HT6 or 5-HT7 receptors (K(i) values > 5000 nM). Although 5-HT6 or 5-HT7 receptor affinity alone does not predict whether or not a drug will have atypical antipsychotic activity, the relatively high affinity of the 5-HT6 receptor for several clozapine- related compounds, in combination with the enrichment of 5-HT6 messenger RNA in the striatum, suggests that the ability of at least some atypical antipsychotic drugs to interact with 5-HT6 receptors may contribute to their lack of extrapyramidal side effects.

Original languageEnglish (US)
Pages (from-to)1403-1410
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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