title: 2-Arylpyrazolo[4,3-d]pyrimidin-7-amino derivatives as new potent and selective human A3 adenosine receptor antagonists. Molecular modeling studies and pharmacological evaluation.
abstract: On the basis of our previously reported 2-arylpyrazolo[4,3-d]pyrimidin-7-ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5-45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors: Lucia
authors: L
authors: Squarcialupi
authors: Vittoria
authors: V
authors: Colotta
authors: Daniela
authors: D
authors: Catarzi
authors: Flavia
authors: F
authors: Varano
authors: Guido
authors: G
authors: Filacchioni
authors: Katia
authors: K
authors: Varani
authors: Carmen
authors: C
authors: Corciulo
authors: Fabrizio
authors: F
authors: Vincenzi
authors: Pier Andrea
authors: PA
authors: Borea
authors: Carla
authors: C
authors: Ghelardini
authors: Lorenzo
authors: L
authors: Di Cesare Mannelli
authors: Antonella
authors: A
authors: Ciancetta
authors: Stefano
authors: S
authors: Moro
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D011743:Pyrimidines; D043684:Receptor, Adenosine A3