Adenosine receptor agonists, partial agonists, & antagonists (U.S. Patent Number 13/479,973)

NIDDK announces the availability of a highly selective A1 adenosine receptor (AR) agonist. This receptor is neuroprotective in ischemic and epileptic models. The A1AR-selective full agonist MRS5474 displayed anticonvulsant activity in vivo in a model of minimal clonic seizures, without toxicity characteristic of other A1AR agonists. Nucleoside docking to a homology model based on recently reported agonist-bound AR structures characterized the interaction of cycloalkylrelated constituents with a small hydrophobic subpocket in the A1AR. Recent advances in specificity to the A1AR encourage development of these agonists for CNS disorders. Work on the structure activity relationship of candidate molecules and the human A1AR revealed that substituents larger than cyclobutyl greatly reduced the AR affinity, and groups that were much larger or smaller than cyclopropyl abolished A1AR selectivity. The group of truncated derivatives that were developed have more drug-like physical properties than other A1AR agonists; this approach is appealing for preclinical development.