The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A₁ and A_2A receptor affinity and selectivity profiles

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 A_2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA_2B and hA₃ 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 A₁ AR affinity (K_i = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (K_i = 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

Disclosure statement

The authors report no declarations of interest.

Funding

The synthetic work was financially supported by the University of Florence, Italy, the Italian Ministry for University and Research (MIUR, PRIN 2010–2011, 20103W4779_004 project). The molecular modeling work coordinated by S.M. was carried out with financial support from the University of Padova, Italy, and the Italian Ministry for University and Research (MIUR), Rome, Italy. S.M. is also very grateful to Chemical Computing Group and to OpenEye for the scientific and technical partnership.