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Eur J Med Chem. 2014 Sep 12;84:614-27. doi: 10.1016/j.ejmech.2014.07.060. Epub 2014 Jul 19.

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.

Author information

  • 1Dipartimento 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.
  • 2Dipartimento 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.
  • 3Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
  • 4Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
  • 5Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.

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.

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

PMID:
25063944
DOI:
10.1016/j.ejmech.2014.07.060
[PubMed - indexed for MEDLINE]
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