Truncated (N)-Methanocarba Nucleosides as A(1) Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a...

A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH(2)OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N(6)-dicyclopropylmethyl, K(i) 47.9 nM). Thus, at the A(1)AR recognition elements for nucleoside binding depend more on 5'region interactions, and in their absence A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR. The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A(1)AR agonists; this approach is appealing for preclinical development.