title: Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors.
abstract: A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki=3.62-57nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki=3.62nM and 18nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki=5.26nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Squarcialupi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falsini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Betti
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. Electronic address: vittoria.colotta@unifi.it.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
mesh_terms: D000586:Amination; D006801:Humans; D062105:Molecular Docking Simulation; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A
keywords: A(1) and A(2A) adenosine receptor antagonists; G protein-coupled receptors; Ligand–adenosine receptor modeling studies; Pyrazolo[4,3-d]pyrimidines