title: 2-Phenylpyrazolo[4,3-d]pyrimidin-7-one as a new scaffold to obtain potent and selective human A3 adenosine receptor antagonists: new insights into the receptor-antagonist recognition.
abstract: A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d]pyrimidin-7-one derivatives as new human A(3) adenosine receptor antagonists. Substituents with different lipophilicity and steric hindrance were introduced at the 5-position of the bicyclic scaffold (R(5) = H, Me, Et, Ph, CH(2)Ph) and on the 2-phenyl ring (OMe, Me). Most of the synthesized derivatives were highly potent hA(3) adenosine receptor antagonists, the best being the 2-(4-methoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-one (K(i) = 1.2 nM). The new compounds were also highly selective, being completely devoid of affinity toward hA(1), hA(2A), and hA(2B) adenosine receptors. On the basis of the recently published human A(2A) receptor crystallographic information, we propose a novel receptor-driven hypothesis to explain both A(3) AR affinity and A(3) versus A(2A) selectivity profiles of these new antagonists.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Università di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Erika
authors.initials: E
authors.lastname: Morizzo
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C030986:pyrimidine