Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A₃ Adenosine Receptors: Affinity Enhancement by <i>N</i>⁶-(2-Phenylethyl) Substitution.

ABSTRACT: Dopamine-derived N⁶-substituents, compared to N⁶-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A₃ adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, K_i = 10.9/17.8 nM, at human/mouse A₃AR). 15 was a partial agonist in vitro (hA₃AR, cAMP inhibition, 31% E_max; mA₃AR, [³⁵S]GTP-γ-S binding, 16% E_max) and in vivo and also antagonized hA₃AR in vitro. Distal H-bonding substitutions of the N⁶-(2-phenylethyl) moiety particularly enhanced mA₃AR affinity by polar interactions with the extracellular loops, predicted usin

SUBMITTER: Tosh DK 

PROVIDER: S-EPMC7443318 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature