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) receptors, and correlation studies have indicated that the clinical efficacy of neuroleptic agents may be coupled to their affinity for D2 receptors. More recently, a family of DA D2-like receptors has been identified. These receptors include the D2A, D2B, D3 and D4 receptors. On the basis of in vitro receptor-binding studies, it has been suggested that the atypical profile of clozapine might be related to a selective effect on the D4 receptor subtype. We have studied the receptor-binding profiles of a series of antipsychotic agents and evaluated some of the compounds in behavioural assays in the rat. Most of the antipsychotic agents lack selectivity for DA-receptors as well as selectivity for the various DA-receptor subtypes. Because of this lack of selectivity, 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 be taken into account in a proper analysis of the clinical profile. Consequently, most speculations on the key-target of clinically interesting antipsychotics (including clozapine) may be of little practical value. Clinical studies with receptor (subtype)-selective agents will be more informative.
Hacksell
U
U
Preclinical R&D, Astra Arcus AB, Södertälje, Sweden.
Jackson
D M
DM
Mohell
N
N
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D011954:Receptors, Dopamine / Q000145:classification*
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine