Truncated (N)-Methanocarba Nucleosides as A1 Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element

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. This modification previously converted A3AR agonists into antagonists, but the comparable effect at A1AR is unknown. In comparison to ribosides, affinity at the A1AR was less well preserved than that at the A3AR, although a few derivatives were moderately A1AR selective, notably full agonist 21 (N6-dicyclopropylmethyl, Ki 47.9 nM). Thus, at the A1AR, recognition elements for nucleoside binding depend more on 5′ region interactions, and in their absence, A3AR 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 A1 but not A3AR. The derivatives ranged from partial to full agonists in A1AR-mediated adenylate cyclase inhibition. Truncated derivatives have more druglike physica...