title: Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors.
abstract: A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Drabczyńska
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Meryem
authors.initials: M
authors.lastname: Köse
authors.affiliation: Institute of General and Ecological Chemistry, Technical University of Łódź, Żwirki 36, 90-924 Łódź, Poland.
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.affiliation: Institute of General and Ecological Chemistry, Technical University of Łódź, Żwirki 36, 90-924 Łódź, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fruziński
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Schabikowski
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Doroz-Płonka
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: mfkonono@cyf-kr.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003412:Cricetulus; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018047:Receptors, Purinergic P1; D014970:Xanthines
keywords: Adenosine receptor; Docking; Homology modeling; Purine-2,6-dione; Species differences; Subtype selectivity; Xanthines