Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. uri icon

abstract

  • The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[ c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6 H-benzo[ c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity. Key pharmacophoric features of the new selective agonists include a 3-(1',1'-dimethylheptyl) side chain and a 6-oxo group on the cannabinoid tricyclic structure that characterizes this class of compounds as "cannabilactones." Our results suggest that the six-membered lactone pharmacophore is critical for CB2 receptor selectivity. Optimal receptor subtype selectivity of 490-fold and subnanomolar affinity for the CB2 receptor is exhibited by a 9-hydroxyl analog 5 (AM1714), while the 9-methoxy analog 4b (AM1710) had a 54-fold CB2 selectivity. X-ray crystallography and molecular modeling show the cannabilactones to have a planar ring conformation. In vitro testing revealed that the novel compounds are CB2 agonists, while in vivo testing of cannabilactones 4b and 5 found them to possess potent peripheral analgesic activity.

published proceedings

  • J Med Chem

altmetric score

  • 9.5

author list (cited authors)

  • Khanolkar, A. D., Lu, D., Ibrahim, M., Duclos, R. I., Thakur, G. A., Malan, T. P., ... Makriyannis, A.

citation count

  • 75

complete list of authors

  • Khanolkar, Atmaram D||Lu, Dai||Ibrahim, Mohab||Duclos, Richard I||Thakur, Ganesh A||Malan, T Phillip||Porreca, Frank||Veerappan, Vijayabaskar||Tian, Xiaoyu||George, Clifford||Parrish, Damon A||Papahatjis, Demetris P||Makriyannis, Alexandros

publication date

  • December 2007