Structural Sweet Spot for A₁ Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

Abstract

A₁ adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of <i>N</i>⁶-cycloalkylmethyl 4′-truncated (N)-methanocarba-adenosines identified <b>10</b> (MRS5474, <i>N</i>⁶-dicyclopropylmethyl, <i>K</i>_i = 47.9 nM) as a moderately A₁AR-selective full agonist. Two stereochemically defined <i>N</i>⁶-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A₁AR selectivity. Nucleoside docking to A₁AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger “A” forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket “B” forming contacts between TM6 and TM7. <b>10</b> suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A₁AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A₁AR agonists. Thus, we identified highly restricted regions for substitution around <i>N</i>⁶ suitable for an A₁AR agonist with anticonvulsant activity