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

摘要

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, [35S]GTP-gamma-S binding, 16% E-max) and in vivo and also antagonized hA,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.