Structure−Activity Relationships of 2,N6,5‘-Substituted Adenosine Derivatives with Potent Activity at the A2BAdenosine Receptor
- 23 March 2007
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 50 (8) , 1810-1827
- https://doi.org/10.1021/jm061278q
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 A2BAR. Simplification, altered connectivity, and mimicking of the indole ring of 17 failed to maintain A2BAR potency. Introduction of N6-ethyl or N6-guanidino substitution, shown to favor A2BAR potency, failed to enhance potency in the 2-(3-(indolyl)ethyloxy)adenosine series. Indole 5‘ ‘- or 6‘ ‘-halo substitution was favored at the A2BAR, but a 5‘-N-ethylcarboxyamide did not further enhance potency. 2-(3‘ ‘-(6‘ ‘-Bromoindolyl)ethyloxy)adenosine 28 displayed an A2BAR 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 A2B and A2AARs 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 A2BAR potency and selectivity.Keywords
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