title: Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.
abstract: The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) 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 D(2) and 5-HT(1A) receptor profile. When the hD(2L) 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 hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) 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 hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.
authors.affiliation: Cellular and Molecular Biology Department, Pierre Fabre Research Center, 17 Avenue Jean Moulin, 81106 Castres Cedex, France. peter.heusler@pierre-fabre.com
authors.forename: Peter
authors.initials: P
authors.lastname: Heusler
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Annabelle
authors.initials: A
authors.lastname: Castro-Fernandez
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008845:Microinjections / Q000379:methods; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; C113776:dopamine D2L receptor