title: Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells.
abstract: Interaction at dopamine D4 receptors may improve cognitive function, which is highly impaired in individuals with schizophrenia, but comparative studies of recent antipsychotics in cellular models of D4 receptor activation are lacking. Here, we report the in-vitro profile of over 30 ligands at recombinant hD4.4 receptors. In [35S]GTPgammaS binding experiments using membranes of CHO-hD4.4 cells, apomorphine, preclamol and the selective D4 agonists, ABT724, CP226269, Ro-10-5824 and PD168077, behaved as partial agonists (Emax 20-60% vs. dopamine), whereas L745870 and RBI257, displayed antagonist properties. The 'conventional' antipsychotic, haloperidol and the 'atypicals', clozapine and risperidone, exhibited antagonist properties, while 'third generation' compounds bifeprunox, SLV313 and F15063, acted as partial agonists (10-30%). Aripiprazole and SSR181507 slightly stimulated [35S]GTPgammaS binding at micromolar concentrations. In Xenopus laevis oocytes co-expressing hD4.4 receptors with G-protein-coupled inwardly rectifying potassium (GIRK) channels, apomorphine, preclamol, ABT724, CP226269, and PD168077 stimulated GIRK currents (Emax 70-80%). The 5-HT1A receptor ligands, WAY100635 and flibanserin, also exhibited partial agonist activity (30% and 15%, respectively). Haloperidol, clozapine, olanzapine and nemonapride did not stimulate GIRK currents, whereas aripiprazole, bifeprunox, SLV313 and F15063, but not SSR181507, exhibited partial agonism (Emax 20-35%). In-vitro responses depended on experimental conditions: increasing NaCl concentration (30 mm to 100 mm) reduced agonist efficacy in [35S]GTPgammaS binding, whereas decreasing the amount of hD4.4 cRNA injected into oocytes (from 2.0 to 0.5 ng/oocyte) reduced agonist efficacy of several compounds. These data indicate that, unlike conventional or 'atypical' antipsychotics, several 'third generation' agents display D4 receptor partial agonism that may be sufficient to influence physiological D4 receptor activity in vivo.
authors: Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France. adrian.newman.tancredi@pierre-fabre.com
authors: Adrian
authors: A
authors: Newman-Tancredi
authors: Peter
authors: P
authors: Heusler
authors: Jean-Claude
authors: JC
authors: Martel
authors: Anne-Marie
authors: AM
authors: Ormière
authors: Nathalie
authors: N
authors: Leduc
authors: Didier
authors: D
authors: Cussac
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007554:Isotopes / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis
chemical_list: D014150:Antipsychotic Agents; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D015259:Dopamine Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007554:Isotopes; D050638:Receptors, Dopamine D4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017242:Complement Factor H