Cannabilactones: A novel class of CB2 selective agonists with peripheral analgesic activity

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

Research output: Contribution to journalArticle

64 Scopus citations

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-6H-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.

Original languageEnglish (US)
Pages (from-to)6493-6500
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number26
DOIs
StatePublished - Dec 27 2007

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Khanolkar, A. D., Lu, D., Ibrahim, M., Duclos, R. I., Thakur, G. A., Malan, T. P., Porreca, F., Veerappan, V., Tian, X., George, C., Parrish, D. A., Papahatjis, D. P., & Makriyannis, A. (2007). Cannabilactones: A novel class of CB2 selective agonists with peripheral analgesic activity. Journal of Medicinal Chemistry, 50(26), 6493-6500. https://doi.org/10.1021/jm070441u