A1 adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A1AR were truncated to eliminate 5'-CH2OH. Similar truncation of nucleosides previously converted A3AR agonists into antagonists, but its effect at A1AR is unknown. In comparison to ribosides, affinity at A1AR was less well preserved than at A3AR, although a few derivatives were moderately A1AR selective, notably a full agonist N6-dicyclopropylmethyl derivative. Thus, at the A1AR, recognition elements for nucleoside binding depend more on 5' region interactions, and in their absence, A3AR selectivity predominates. Based on a recently reported agonist-bound AR x-ray structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A1 but not A3AR. The derivatives ranged from partial to full agonists in A1AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A1AR agonists; this approach is appealing for preclinical development.

Discovery of truncated (N)-methanocarba nucleosides as A<sub>1</sub> adenosine receptor agonists

243rd National Meeting (2012)

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Discovery of truncated (N)-methanocarba nucleosides as A1 adenosine receptor agonists

Discovery of truncated (N)-methanocarba nucleosides as A₁ adenosine receptor agonists