The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles |
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| Authors: | Lucia Squarcialupi Marco Betti Daniela Catarzi Flavia Varano Matteo Falsini Annalisa Ravani |
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| Affiliation: | 1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Sesto Fiorentino, Italy;2. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy |
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| Abstract: | New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki =?150?nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki =?123?nM) and A1 AR affinity (Ki =?25?nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki =?11?nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15–24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis. | |
| Keywords: | Adenosine A1 and A2A receptor antagonists G protein-coupled receptors ligand-receptor modeling studies pyrazolo[4,3-d]pyrimidines |
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