Received for publication July 7, 2005.
Revised August 30, 2005.
Accepted for publication August 30, 2005.

Intrinsic Efficacy of Antipsychotics at Human D₂, D₃, and D₄ Dopamine Receptors: Identification of the clozapine metabolite N-desmethylclozapine as a D₂/D₃ partial agonist

Abstract

Drugs that antagonize D₂-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The 'atypical' antipsychotics have a lower propensity to cause extra-pyramidal symptoms (EPS) but the molecular basis for this is not fully understood, nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay we demonstrate that overexpression of Go induces constitutive activity in the human D₂-like receptors (D₂, D₃ and D₄). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D₂ and D₃ inverse agonists, whereas none were D₄ inverse agonists, though many were potent D₄ antagonists. The inverse agonist activity of haloperidol at D₂ and D₃ receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole, and the principle active metabolite of clozapine, N-desmethylclozapine (NDMC) were identified as partial agonists at D₂ and D₃ receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole use may be due, in part, to these partial agonist properties of NDMC and aripiprazole, and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.

Key words: G protein, antipsychotic, constitutive activity, dopamine receptor, inverse agonist, partial agonist

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