Structure−Activity Relationships of 2,N6,5‘-Substituted Adenosine Derivatives with Potent Activity at the A2B Adenosine Receptor

Abstract

2, N⁶, and 5‘-substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-arylalkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was examined in both binding and cAMP assays and found to be a potent agonist of the human A_2BAR. Simplification, altered connectivity, and mimicking of the indole ring of 17 failed to maintain A_2BAR potency. Introduction of N⁶-ethyl or N⁶-guanidino substitution, shown to favor A_2BAR potency, failed to enhance potency in the 2-(3-(indolyl)ethyloxy)adenosine series. Indole 5‘ ‘- or 6‘ ‘-halo substitution was favored at the A_2BAR, but a 5‘-N-ethylcarboxyamide did not further enhance potency. 2-(3‘ ‘-(6‘ ‘-Bromoindolyl)ethyloxy)adenosine 28 displayed an A_2BAR EC₅₀ value of 128 nM, that is, more potent than the parent 17 (299 nM) and similar to 5‘-N-ethylcarboxamidoadenosine (140 nM). Compound 28 was a full agonist at A_2B and A_2AARs and a low efficacy partial agonist at A₁ and A₃ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A_2BAR potency and selectivity.