Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

Substitution of rigidified A(3) adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-y1)ethynyl) or a 2-(4-(5-chlorothiophen-2-y1)-1H-1,2,3-triazol-1-yl)) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N-6-Small alkyl derivatives were newly optimized for A(3)AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N-6-ethyl alkyne 20 (MRS7144, K-i 1.7 nM) and 1-aza N-6-propyl alkyne 12 (MRS7154, K-i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A(3)AR affinity, selectivity, and efficacy.