The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A and A receptor affinity and selectivity profiles.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY(2017)
Abstract
New 7-amino-2-phenylpyrazolo[ 4,3-d] pyrimidine derivatives, substituted at the 5-position with aryl(alkyl) a-mino- and 4-substituted-piperazin-1-yl-moieties, were synthesized with the aim of targeting human (h) adenosine A(1) and/or A(2A) receptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA(2B) and hA(3) ARs. The 5-(4-hydroxyphenethylamino)-derivative 12 showed both good affinity (K-i = 150 nM) and the best selectivity for the hA(2A) AR while the 5-benzylamino-substituted 5 displayed the best combined hA(2A) (K-i = 123 nM) and A(1) AR affinity (K-i = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (K-i = 11 nM) and good selectivity for the hA(1) AR. The 5-(N-4-substituted-piperazin-1-yl) derivatives 15-24 bind the hA(1) 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.
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Key words
Adenosine A1 and A2A receptor antagonists,G protein-coupled receptors,ligand-receptor modeling studies,pyrazolo[4,3-d]pyrimidines
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