Mixed agonist-antagonist properties of clozapine at different human clonedmuscarinic receptor subtypes expressed in Chinese hamster ovary cells

We recently reported that clozapine behaves as a partial agonist at the clo ned human m4 muscarinic receptor subtype. In the present study, we investig ated whether the drug could elicit similar effects at the cloned human m1, m2, and m3 muscarinic receptor subtypes expressed in the Chinese hamster ov ary (CHO) cells. Clozapine elicited a concentration-dependent stimulation o f [H-3]inositol phosphates accumulation in CHO cells expressing either the m1 or the m3 receptor subtype. Moreover, clozapine inhibited forskolin-stim ulated cyclic AMP accumulation and enhanced [S-35] GTP gamma S binding to m embrane G proteins in CHO cells expressing the m2 receptor. These agonist e ffects of clozapine were antagonized by atropine. The intrinsic activity of clozapine was lower than that of the full cholinergic agonist carbachol, a nd, when the compounds were combined, clozapine potently reduced the recept or responses to carbachol. These data indicate that clozapine behaves as a partial agonist at different muscarinic receptor subtypes and may provide n e su hints for understanding the receptor mechanisms underlying the antipsy chotic efficacy of the drug. [Neuropsychopharmacology 20:263-270, 1999] (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Sc ience Inc.