title: Functional characterization of the novel antipsychotic iloperidone at human D2, D3, alpha 2C, 5-HT6, and 5-HT1A receptors.
abstract: Iloperidone has demonstrated an interesting monoamine receptor profile in radioligand binding studies, with nanomolar affinity for certain noradrenaline, dopamine, and serotonin receptors. In this study, the agonist/antagonist activity of iloperidone was determined in cell lines expressing recombinant human D(2A), D(3), alpha(2C), 5-HT(1A), or 5-HT(6) receptors. With the exception of 5-HT(6) receptors, these receptors are negatively coupled to cyclase. Thus, after stimulation with forskolin, the agonists dopamine (at D(2A) and D(3)), noradrenaline (at alpha(2C)), or 8-OH-DPAT (at 5-HT(1A)) induced a reduction in cAMP accumulation. Conversely, activation of the 5-HT(6) receptor by 5-HT led to an increase in cAMP accumulation. Iloperidone alone was devoid of significant agonist activity but inhibited the agonist response in all 5 cell lines in a surmountable and concentration-dependent fashion. Iloperidone was most potent at D(3) receptors (pK(B) 8.59 +/- 0.20; n = 6), followed by alpha(2C) (pK(B) 7.83 +/- 0.06; n = 15), 5-HT(1A) (pK(B) 7.69 +/- 0.18; n = 10), D(2A) (pK(B) 7.53 +/- 0.04; n = 11) and 5-HT(6) (pK(B) 7.11 +/- 0.08; n = 11) receptors.
authors.affiliation: Novartis Pharma AG, Research Nervous System, Building S-360-405 CH-4002 Basel, Switzerland. hans.kalkman@pharma.novartis.com
authors.forename: Hans O
authors.initials: HO
authors.lastname: Kalkman
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.forename: Erika
authors.initials: E
authors.lastname: Lötscher
authors.forename: Philippe
authors.initials: P
authors.lastname: Schoeffter
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D017982:Receptors, Biogenic Amine / Q000378:metabolism; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007555:Isoxazoles; D010880:Piperidines; D017982:Receptors, Biogenic Amine; D000242:Cyclic AMP; C081732:iloperidone