Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A adenosine receptor antagonists.

Recognition of nucleosides at adenosine receptors (ARs) is supported by multiple X-ray structures, but the structure of an adenine complex is unknown. We examined the selectivity of predicted AAR and AAR adenine antagonists that incorporated known agonist affinity-enhancing and C2 substituents. Adenines with AAR-favoring -alkyl, cycloalkyl and arylalkyl substitutions combined with an AAR-favoring 2-((5-chlorothiophen-2-yl)ethynyl) group were human (h) AAR-selective, MRS7497 (∼1000-fold over AAR). In addition, binding selectivity over hAAR and hAAR and functional AAR antagonism were demonstrated. was subjected to computational docking and molecular dynamics simulation in a hAAR homology model to predict interactions. The SAR of nucleoside AR agonists was not recapitulated in adenine AR antagonists, and modeling suggested an alternative, inverted binding mode with the key N250 H-bonding to the adenine and , instead of and as in adenosine agonists.