title: Structure-activity relationships of 2,N(6),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 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.
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
authors: Hayamitsu
authors: H
authors: Adachi
authors: Krishnan K
authors: KK
authors: Palaniappan
authors: Andrei A
authors: AA
authors: Ivanov
authors: Nathaniel
authors: N
authors: Bergman
authors: Zhan-Guo
authors: ZG
authors: Gao
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C520343:2-(3''-(6''-bromoindolyl)ethyloxy)adenosine; D058908:Adenosine A2 Receptor Agonists; D000242:Cyclic AMP; D000241:Adenosine