title: N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors.
abstract: Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose.
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: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: Britta
authors.initials: B
authors.lastname: Schumacher
authors.forename: Anke
authors.initials: A
authors.lastname: Schiedel
authors.forename: Olga
authors.initials: O
authors.lastname: Yuzlenko
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry*; D016466:CHO Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D011407:Propane / Q000737:chemistry*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011687:Purines; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D001554:Benzene; C030986:pyrimidine; D011407:Propane; C030985:purine