CLOZAPINE IS A POTENT AND SELECTIVE MUSCARINIC M(4) RECEPTOR AGONIST

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.