title: Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones.
abstract: Syntheses and physicochemical properties of N-aryl-substituted imidazo-, pyrimido-, and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-haloalkyl-8-bromo-1,3-dimethyl- or 1,3-dipropyl-xanthine derivatives with corresponding arylamines. The obtained compounds (1-40), which can be envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were additionally investigated for affinity to the A(2B) and A(3) receptor subtypes. Many of the compounds showed adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations and were A(2A)-selective, for example, compound 23 with p-fluoro substituent displayed K(i) value of 0.147 microM at the rat A(2A) receptor and more than 170-fold-A(2A) selectivity, compound 17 with naphthyl substituent had K(i) value of 0.219 microM and a more than 114-fold-A(2A) selectivity. The compounds were somewhat weaker and less selective at the human receptor subtypes. Elongation of the dimethyl substituent to dipropyl in xanthine moiety improved affinity but reduced selectivity. 1,3-Dimethylimidazo-, pyrimido-, and diazepinopurinediones were evaluated in vivo as anticonvulsants in MES, ScMet, TTE tests and examined for neurotoxicity in mice (ip). Substances with pyrimido ring displayed protective activity in ScMet or in MES and ScMet tests, showing also neurotoxicity. The pyrimidine annelated ring is beneficial for both receptor affinity and anticonvulsant activity.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, Pl 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Drabczyńska
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Svenja K
authors.initials: SK
authors.lastname: Lacher
authors.forename: Britta
authors.initials: B
authors.lastname: Schumacher
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: Antony
authors.initials: A
authors.lastname: Nasal
authors.forename: Piotr
authors.initials: P
authors.lastname: Kawczak
authors.forename: Olga
authors.initials: O
authors.lastname: Yuzlenko
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pekala
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D011687:Purines; D018047:Receptors, Purinergic P1