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Cannabilactones: A Novel Class of CB2 Selective Agonists with Peripheral Analgesic Activity

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Center for Drug Discovery, Northeastern University, 116 Mugar Hall, 360 Huntington Avenue, Boston, Massachusetts 02115-5000, Departments of Anesthesiology and Pharmacology, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, Arizona 85724-5114, Naval Research Laboratory, Code 6030, 4555 Overlook Avenue, Washington, DC 20375-5341, and Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vass. Constantinou, Athens 116-35 Greece
* To whom correspondence should be addressed Tel.: 1-617-373-4200 . Fax: 1-617-373-7493. E-mail: [email protected]
†Northeastern University.
‡University of Arizona College of Medicine.
§Naval Research Laboratory.
∥National Hellenic Research Foundation.
Cite this: J. Med. Chem. 2007, 50, 26, 6493–6500
Publication Date (Web):November 27, 2007
https://doi.org/10.1021/jm070441u
Copyright © 2007 American Chemical Society

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    Abstract

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    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.

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    Elemental analyses data and X-ray diffraction data for 4a and 4b. This material is available free of charge via the Internet at .

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