title: Iloperidone binding to human and rat dopamine and 5-HT receptors.
abstract: Iloperidone (HP 873; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl]ethanone) is a compound currently in clinical trials for the treatment of schizophrenia. Iloperidone displays affinity for dopamine D2 receptors and for 5-HT2A receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic. Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes. We employed receptor binding assays using membranes from cells stably expressing human dopamine D1, D2S, D2L, D3, D4 and D5 and 5-HT2A and 5-HT2C receptors and rat 5-HT6 and 5-HT7 receptors. Iloperidone displayed higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than for the dopamine D4 receptor (Ki = 25 nM). Iloperidone displayed high affinity for the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively), and was found to have higher affinity for the 5-HT2A (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM). The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds.
authors.affiliation: Neuroscience Research, Hoechst Marion Roussel, Inc., Bridgewater, NJ 08807-0800, USA. KONGSAM1@brwhcc3.hcc.com
authors.forename: S
authors.initials: S
authors.lastname: Kongsamut
authors.forename: J E
authors.initials: JE
authors.lastname: Roehr
authors.forename: J
authors.initials: J
authors.lastname: Cai
authors.forename: H B
authors.initials: HB
authors.lastname: Hartman
authors.forename: P
authors.initials: P
authors.lastname: Weissensee
authors.forename: L L
authors.initials: LL
authors.lastname: Kerman
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.forename: A
authors.initials: A
authors.lastname: Sandrasagra
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000378:metabolism*; D001480:Basal Ganglia Diseases / Q000503:physiopathology; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000378:metabolism*; D007700:Kinetics; D010880:Piperidines / Q000009:adverse effects / Q000378:metabolism*; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; C493593:DRD3 protein, human; C493599:DRD4 protein, human; C493605:DRD5 protein, human; C493595:Drd3 protein, rat; C493601:Drd4 protein, rat; C493607:Drd5 protein, rat; D007555:Isoxazoles; D010880:Piperidines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; C081732:iloperidone