Richard S. Priestley
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.
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|
|Publisher||Federation of American Society of Experimental Biology|
|Peer Reviewed||Peer Reviewed|
|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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