Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity.
作者： Dilip K. Tosh , Silvia Paoletta , Francesca Deflorian , Khai Phan , Steven M. Moss
DOI: 10.1021/JM300965A
关键词:
摘要: A1 adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N6-cycloalkylmethyl 4′-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N6-dicyclopropylmethyl, Ki = 47.9 nM) as a moderately A1AR-selective full agonist. Two stereochemically defined N6-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, those or smaller cyclopropyl A1AR selectivity. Nucleoside docking to homology model characterized distinct hydrophobic subpockets, the “A” forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), carbon chains glutamates (EL2) subpocket “B” between TM6 TM7. suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment agonists. Truncated nucleosides, an appealing preclinical approach,...
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