title: Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors.
abstract: Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodźki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO 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 Chemistry, Siedlce University, 3 Maja 54 St., PL-08110 Siedlce, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Karczmarzyk
authors.affiliation: Institute of General and Ecological Chemistry, Technical University, Żeromskiego115 St.,PL-90924 Łódź, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fruziński
authors.affiliation: Department of Chemistry, University of Turku, Vatselankatu 2, FI-20014 Turku, Finland.
authors.forename: Kalevi
authors.initials: K
authors.lastname: Pihlaja
authors.affiliation: Department of Chemistry, University of Turku, Vatselankatu 2, FI-20014 Turku, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Sinkkonen
authors.affiliation: Department of Chemistry, University of Turku, Vatselankatu 2, FI-20014 Turku, Finland.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Wiinämaki
authors.affiliation: Biotie Therapie GmbH, Meissner Str. 191, DE-01445 Radebul, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kronbach
authors.affiliation: Biotie Therapie GmbH, Meissner Str. 191, DE-01445 Radebul, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Unverferth
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4A Chodźki St., PL-20093 Lublin, Poland. Electronic address: darek.matosiuk@umlub.pl.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Matosiuk
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097806:GluK2 Kainate Receptor
chemical_list: D007211:Indoles; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor
keywords: Homology modeling; Indole derivatives; Kainate receptors; Molecular docking; X-ray structure determination