title: Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones.
abstract: Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A(1) and A(2A) receptors. Selected compounds were additionally investigated for affinity to the human A(1), A(2A), A(2B) and A(3) receptor subtypes. The results of the radioligand binding assays at adenosine A(1) and A(2A) receptors showed that most of the compounds exhibited adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A(2A) affinity. The most potent A(2A) ligands of the present series were compounds 6 (K(i) 0.33 μM rat A(2A), 0.31 μM human A(2A)), 8 (K(i) 0.98 μM rat A(2A), 0.42 μM human A(2A)) and 15 (K(i) 0.24 μM rat A(2A), 0.61 μM human A(2A)) with the latter one showing high A(2A) selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A(2A) receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q(2) = 0.88) for A(2A) AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A(2A) antagonists with good water-solubility.
authors.affiliation: Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Drabczyńska
authors.forename: Olga
authors.initials: O
authors.lastname: Yuzlenko
authors.forename: Meryem
authors.initials: M
authors.lastname: Köse
authors.forename: Minka
authors.initials: M
authors.lastname: Paskaleva
authors.forename: Anke C
authors.initials: AC
authors.lastname: Schiedel
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuder
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003500:Cyclization; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects
chemical_list: D011687:Purines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A