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A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

Priestley, Richard S.; Nickolls, Sarah A.; Alexander, Stephen P. H.; Kendall, David A.


Richard S. Priestley

Sarah A. Nickolls

Stephen P. H. Alexander

David A. Kendall


Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-alpha agonist fenofibrate exhibited submicromolar affinity for both receptors (pKi CB1, 6.3 +/- 0.1; CB2, 7.7 +/- 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC50, 7.7 +/- 0.1) and a partial agonist at the CB1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [(3)H]-CP55940 at the CB1 receptor, (kfast without: 1.2 +/- 0.2/min; with: 3.8 +/- 0.1 x 10(-2)/min) and decrease the maximal response to CP55940 (Rmax, 86 +/- 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB1 receptors (pEC50, 6.0 +/- 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target.

Journal Article Type Article
Publication Date Apr 1, 2015
Journal The FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 1530-6860
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 29
Issue 4
Pages 1446-1455
APA6 Citation Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., & Kendall, D. A. (2015). A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB Journal, 29(4), 1446-1455. doi:10.1096/fj.14-263053
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