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Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity.
J Med Chem. 2007 Dec 27; 50(26):6493-500.JM

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.

Authors+Show Affiliations

Center for Drug Discovery, Northeastern University, 116 Mugar Hall, 360 Huntington Avenue, Boston, Massachusetts 02115-5000, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18038967

Citation

Khanolkar, Atmaram D., et al. "Cannabilactones: a Novel Class of CB2 Selective Agonists With Peripheral Analgesic Activity." Journal of Medicinal Chemistry, vol. 50, no. 26, 2007, pp. 6493-500.
Khanolkar AD, Lu D, Ibrahim M, et al. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J Med Chem. 2007;50(26):6493-500.
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), 6493-500.
Khanolkar AD, et al. Cannabilactones: a Novel Class of CB2 Selective Agonists With Peripheral Analgesic Activity. J Med Chem. 2007 Dec 27;50(26):6493-500. PubMed PMID: 18038967.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. AU - Khanolkar,Atmaram D, AU - Lu,Dai, AU - Ibrahim,Mohab, AU - Duclos,Richard I,Jr AU - Thakur,Ganesh A, AU - Malan,T Phillip,Jr AU - Porreca,Frank, AU - Veerappan,Vijayabaskar, AU - Tian,Xiaoyu, AU - George,Clifford, AU - Parrish,Damon A, AU - Papahatjis,Demetris P, AU - Makriyannis,Alexandros, Y1 - 2007/11/27/ PY - 2007/11/28/pubmed PY - 2008/4/4/medline PY - 2007/11/28/entrez SP - 6493 EP - 500 JF - Journal of medicinal chemistry JO - J Med Chem VL - 50 IS - 26 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/18038967/Cannabilactones:_a_novel_class_of_CB2_selective_agonists_with_peripheral_analgesic_activity_ L2 - https://doi.org/10.1021/jm070441u DB - PRIME DP - Unbound Medicine ER -