Truncated (N)-methanocarba ([3.1.0]bicyclohexyl) adenosines were synthesized and shown to bind selectively to mouse (m) and human (h) A3 adenosine receptors (ARs). A N6-2-((4-hydroxy-3-methoxy)-phenyl)ethyl group was conducive to high affinity and selectivity, e.g. C2-phenylethynyl analogue (MRS7591, 15) with A3AR binding Ki values of 10.9 (h) and 17.8 (m) nM. 15 was a low efficacy partial agonist at mA3AR (guanine nucleotide binding, 16%) and hA3AR (cyclic AMP inhibition, 31%). Combination of the N6-3-O-methyldopamine substitution with a C2-(5-bromothien-2-yl-ethynyl) group (MRS7653, 30) provided 1000-fold A3AR selectivity. Thus, we have greatly increased mA3AR affinity and selectivity in this series using a dopamine-derived N6 substituent. However, combination of N6-3-O-methyldopamine substitution of 15 with a C2-(2-fluorophenylethynyl) group (17) or 4-O-methylation in 16 enhanced hA1AR affinity. Computational modeling using mA3AR and hA3AR homology models has provided a hypothesis for the recognition of 15 and its congeners, with the nucleoside moiety binding similarly to A1AR or A2AAR agonists in X-ray crystallographic structures, but focusing on potential distal polar interactions with extracellular loops consistent with the enhanced affinity of 15 at mA3AR.

Truncated (N)-methanocarba nucleosides as partial agonists at mouse and human A3 adenosine receptors: Affinity enhancement by N6-(2-phenylethyl) substitution

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.