title: Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity.
abstract: A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N(6)-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N(6)-dicyclopropylmethyl, K(i) = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N(6)-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR 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. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N(6) suitable for an A(1)AR agonist with anticonvulsant activity.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Steven M
authors.initials: SM
authors.lastname: Moss
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D009705:Nucleosides; D043682:Receptor, Adenosine A1