DOES THE DOPAMINE-RECEPTOR SUBTYPE SELECTIVITY OF ANTIPSYCHOTIC AGENTS PROVIDE USEFUL LEADS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC AGENTS

Antipsychotic agents share the ability to antagonize dopamine (DA) rec eptors, and correlation studies have indicated that the clinical effic acy of neuroleptic agents may be coupled to their affinity for D-2 rec eptors. More recently, a family of DA D-2-like receptors has been iden tified. These receptors include the D-2A, D-2B D-3 and D-4 receptors. On the basis of in vitro receptor-binding studies, it has been suggest ed that the atypical profile of clozapine might be related to a select ive effect on the D-4 receptor subtype. We have studied the receptor-b inding profiles of a series of antipsychotic agents and evaluated some of the compounds in behavioural assays in the rat. Most of the antips ychotic agents lack selectivity for DA-receptors as well as selectivit y for the various DA-receptor subtypes. Because of this lack of select ivity it is impossible to draw firm conclusions about the role of any particular receptor in the clinical profile of the neuroleptic agents. Furthermore, the pharmacology of potential human metabolites has to b e taken into account in a proper analysis of the clinical profile. Con sequently, most speculations on the key-target of clinically interesti ng antipsychotics (including clozapine) may be of little practical val ue. Clinical studies with receptor (subtype)-selective agents will be more informative.