title: In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic.
abstract: Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only a half of patients; (3) they have severe side effects including neurological and metabolic side effects. Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2 receptor antagonist, D2AAK1, with Ki of 58 nM using structure-based virtual screening. D2AAK1 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A and 5-HT2A receptors, making it an ideal candidate for a multi-target drug. Here we present homology modeling, molecular docking and molecular dynamics of D2AAK1 and its molecular targets and animal studies of D2AAK1 as a potential antipsychotic. The main contact of D2AAK1 and all the receptors studied is the electrostatic interaction between the protonable nitrogen atom of the ligand and the conserved Asp(3.32) as typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial agonistic properties of D2AAK1 towards all the receptors in in vitro essays and in in silico studies as the ligand stabilizes the ionic lock interaction. We also demonstrated neuroleptic, anxiolytic and, importantly, procognitive properties of D2AAK1 in mouse models.
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: agnieszka.kaczor@umlub.pl.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Budzyńska
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Biała
authors.affiliation: Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain.
authors.forename: Marián
authors.initials: M
authors.lastname: Castro
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D065127:Dopamine D2 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation / Q000379:methods*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A
keywords: Antipsychotics; Behavioral studies; Homology modeling; Molecular docking; Molecular dynamics; Schizophrenia