DOPAMINE-D(4) VERSUS DOPAMINE D(2) RECEPTOR SELECTIVITY OF DOPAMINE RECEPTOR ANTAGONISTS - POSSIBLE THERAPEUTIC IMPLICATIONS

The dopamine D4 receptor, which is considered a close variant of the d opamine D2 receptor, has recently been cloned. Receptor binding studie s demonstrated that clozapine, which is an effective antipsychotic age nt but atypical in that it lacks the usual side effects of other antip sychotic agents, has high selectivity for the dopamine D4 receptor ver sus the dopamine D2 receptor. Comparative binding affinity studies hav e been carried out for a number of interesting dopaminergic agents usi ng membranes prepared from cloned dopamine D2 and D4 receptor containi ng cells. It was found that clozapine is selective for the dopamine D4 vs. the D2 receptor by a factor of 2.8. Other compounds with dopamine D4 receptor selectivity were (+)-apomorphine (8.7), (+)-N-propyl-nora pomorphine (NPA) (2.4) and melperone (1.3). Compounds with considerabl e selectivity for the dopamine D2 receptor were haloperidol (0.31), ch lorpromazine (0.084), trifluoperazine (0.034) and raclopride (0.001). Overall, the results with the antipsychotic agents tested, support the concept that dopamine D4 receptor selectivity may confer clozapine-li ke antipsychotic efficacy and furthermore that dopamine D2 receptor se lectivity may confer side effect liability (extrapyramidal side effect s and tardive dyskinesia).