Selective dopamine/serotonin receptors mediate actions of newer antipsychotic agents

Abstract

The D2 dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D2long (hD2L) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes – typical, atypical, and a “new generation” of compounds, exhibiting a preferential D2 and 5-HT1A receptor profile.When the hD2L receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (−)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD2L receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD2L receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D2/5-HT1A antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties.Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD2L receptor. These differential properties may translate to distinct therapeutic potential of these compounds.