European Journal of Pharmacology 1993-04-15

Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists.

M Kuoppamäki, E Syvälahti, J Hietala

Index: Eur. J. Pharmacol. 245 , 179-182, (1993)

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Abstract

The effects of the atypical antipsychotic drug, clozapine, and its two major metabolites in man, N-desmethylclozapine and clozapine N-oxide, on 5-HT1C receptor mediated phosphoinositide hydrolysis were studied in rat choroid plexus. Clozapine and N-desmethylclozapine antagonized 5-HT-stimulated phosphoinositide hydrolysis with IC50 values of 110 and 29.4 nM, respectively. Clozapine N-oxide was less potent. None of the compounds stimulated phosphoinositide hydrolysis per se. The Ki values for [3H]mesulergine displacement in choroid plexus were in accordance with phosphoinositide hydrolysis data. In conclusion, this study demonstrates that clozapine and one of its major metabolites in man, N-desmethylclozapine, are potent 5-HT1C receptor antagonists. These properties of clozapine and N-desmethylclozapine should be considered when the atypical effects of clozapine are evaluated in vivo.