title: New 2-heterocyclyl-imidazo[2,1-i]purin-5-one derivatives as potent and selective human A3 adenosine receptor antagonists.
abstract: A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A(1), A(2A), and A(3) adenosine receptors. Efficacy at the hA(2B) AR and antagonism of selected ligands at the hA(3) AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA(3) AR (K(i) values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A(1), A(2A), and A(2B) AR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K(i) hA(3) = 1.46 nM, K(i) hA(2A)/K(i) hA(3) > 3425; IC(50) hA(2B)/K(i) hA(3) > 3425; K(i) hA(1)/K(i) hA(3) = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. baraldi@dns.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Abdel Naser
authors.initials: AN
authors.lastname: Zaid
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C561636:4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo(2,1-i)purin-5(4H)-one; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011687:Purines; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D000242:Cyclic AMP