Figure 6.

Structures of the two A₃AR-selective agonists used in the study. (a) IB-MECA is a 9-riboside derivative, a structural feature shared with native adenosine. (b) The more potent and selective agonist MRS3558 contains a modified methanocarba ring system in place of ribose. The methanocarba substitution consists of fused cyclopentane and cyclopropane rings, which serve to constrain this moiety in a conformation that is preferred in the A₃AR binding site. Both analogs share the N6-benzyl-type substitution, which is particularly suited for high affinity at the A₃AR in various species. The methylamide moiety attached at the 4'-position serves to increase A₃AR affinity and to maintain full efficacy in A₃AR activation. The 2-chloro substitution of MRS3558 enhances A₃AR affinity and selectivity. AR, adenosine receptor.