Clozapine is a potent and selective muscarinic M 4 receptor agonist

Abstract

Clozapine was studied in functional assays at human muscarinic M 1−M 5 receptors expressed in Chinese hamster ovary cells. Clozapine was a full agonist at the muscarinic M 4 receptor (EC 50 = 11 nM), producing inhibition of forskolin-stimulated cAMP accumulation. In contrast, clozapine potently antagonized agonist-induced responses at the other four muscarinic receptor subtypes. Selective stimulation of M 4 receptors may, in part, explain the hypersalivation observed clinically with clozapine. Moreover, the unique overall muscarinic profile of clozapine may contribute to its atypical antipsychotic efficacy.