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

Drugs that antagonize D-2- 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 extrapyramidal 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 G alpha(o) induces constitutive activity in the human D-2-like receptors (D-2, D-3, and D-4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D-2 and D-3 inverse agonists, whereas none was D-4 inverse agonist, although many were potent D-4 antagonists. The inverse agonist activity of haloperidol at D-2 and D-3 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 NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D-2 and D-3 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 used 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.