Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity

J Med Chem. 2012 Sep 27;55(18):8075-90. doi: 10.1021/jm300965a. Epub 2012 Sep 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry
  • Anticonvulsants / metabolism*
  • Anticonvulsants / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation*
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / metabolism*
  • Nucleosides / pharmacology*
  • Protein Conformation
  • Receptor, Adenosine A1 / chemistry
  • Receptor, Adenosine A1 / metabolism*
  • Structure-Activity Relationship


  • Anticonvulsants
  • Nucleosides
  • Receptor, Adenosine A1