Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A 3 Adenosine Receptors: Affinity Enhancement by N 6 -(2-Phenylethyl) Substitution.

Dopamine-derived N ⁶ -substituents, compared to N ⁶ -(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A ₃ adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, K _i = 10.9/17.8 nM, at human/mouse A ₃ AR). 15 was a partial agonist in vitro (hA ₃ AR, cAMP inhibition, 31% E _max ; mA ₃ AR, [ ³⁵ S]GTP-γ-S binding, 16% E _max ) and in vivo and also antagonized hA ₃ AR in vitro. Distal H-bonding substitutions of the N ⁶ -(2-phenylethyl) moiety particularly enhanced mA ₃ AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA ₃ AR and hA ₃ AR homology models. These hybrid models were based on an inactive antagonist-bound hA ₁ AR structure for the upper part of TM2 and an agonist-bound hA _2A AR structure for the remaining TM portions. These species-independent A ₃ AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A ₃ AR, a drug target of growing interest.