title: 7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: structural investigations at the 5-position to target human A₁ and A(2A) adenosine receptors. Molecular modeling and pharmacological studies.
abstract: In previous research, several 7-amino-2-arylpyrazolo[4,3-d]pyrimidine derivatives were identified as highly potent and selective antagonists at the human A3 adenosine receptor. Structure-activity relationship studies highlighted that affinity and selectivity depended on the nature of the substituents at the 5- and 7-positions of the pyrazolo[4,3-d]pyrimidine scaffold. In particular, small lipophilic residues at the 5-position and a free amino group at position 7 afforded compounds able to bind all four human (h) adenosine receptors. Hence, to shift affinity toward the hA1 and/or hA(2A) subtypes, alkyl and arylalkyl chains of different length were appended at position 5 of the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amine. Among the new compounds, a dual hA1/hA(2A) receptor antagonist was identified, namely the 5-(3-phenylpropyl) derivative 25, which shows high affinity both at human A1 (K(i) = 5.31 nM) and A(2A) (K(i) = 55 nM) receptors. We also obtained some potent and selective antagonists for the A1 receptor, such as the 5-(3-arylpropyl)-substituted compounds 26-31, whose affinities fall in the low nanomolar range (K(i) = 0.15-18 nM). Through an in silico receptor-driven approach, the obtained binding data were rationalized and the molecular bases of the hA1 and hA(2A) AR affinity and selectivity of derivatives 25-31 are 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: 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. Electronic address: vittoria.colotta@unifi.it.
authors: Vittoria
authors: V
authors: Colotta
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: Daniela
authors: D
authors: Catarzi
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: Flavia
authors: F
authors: Varano
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: Marco
authors: M
authors: Betti
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Katia
authors: K
authors: Varani
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Fabrizio
authors: F
authors: Vincenzi
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Pier Andrea
authors: PA
authors: Borea
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors: Nicola
authors: N
authors: Porta
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors: Antonella
authors: A
authors: Ciancetta
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.
authors: Stefano
authors: S
authors: Moro
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A
keywords: A(1) and A(2A) adenosine receptor antagonists; Dual A(1)/A(2A) adenosine receptor antagonists; G protein-coupled receptors; Ligand–adenosine receptor modeling studies; Pyrazolo[4,3-d]pyrimidines