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. Structureeactivity 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 hA2A 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/hA2A receptor antagonist was identified, namely the 5- (3-phenylpropyl) derivative 25, which shows high affinity both at human A1 (Ki ¼ 5.31 nM) and A2A (Ki ¼ 55 nM) receptors. We also obtained some potent and selective antagonists for the A1 receptor, such as the 5-(3-arylpropyl)-substituted compounds 26e31, whose affinities fall in the low nanomolar range (Ki ¼ 0.15e18 nM). Through an in silico receptor-driven approach, the obtained binding data were rationalized and the molecular bases of the hA1 and hA2A AR affinity and selectivity of derivatives 25e31 are explained.

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies / Lucia Squarcialupi; Vittoria Colotta; Daniela Catarzi; Flavia Varano; Betti Marco; Katia Varani; Fabrizio Vincenzi; Pier Andrea Borea; Nicola Porta; Antonella Ciancetta; Stefano Moro. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 84:(2014), pp. 614-627. [10.1016/j.ejmech.2014.07.060]

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

SQUARCIALUPI, LUCIA;COLOTTA, VITTORIA;CATARZI, DANIELA;VARANO, FLAVIA;BETTI, MARCO;
2014

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. Structureeactivity 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 hA2A 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/hA2A receptor antagonist was identified, namely the 5- (3-phenylpropyl) derivative 25, which shows high affinity both at human A1 (Ki ¼ 5.31 nM) and A2A (Ki ¼ 55 nM) receptors. We also obtained some potent and selective antagonists for the A1 receptor, such as the 5-(3-arylpropyl)-substituted compounds 26e31, whose affinities fall in the low nanomolar range (Ki ¼ 0.15e18 nM). Through an in silico receptor-driven approach, the obtained binding data were rationalized and the molecular bases of the hA1 and hA2A AR affinity and selectivity of derivatives 25e31 are explained.
2014
84
614
627
Lucia Squarcialupi; Vittoria Colotta; Daniela Catarzi; Flavia Varano; Betti Marco; Katia Varani; Fabrizio Vincenzi; Pier Andrea Borea; Nicola Porta; A...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/965232
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