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

作者：Priestley Richard S; Nickolls Sarah A; Alexander Stephen P H; Kendall David A^*

来源：The FASEB Journal, 2015, 29(4): 1446-1455.

DOI：10.1096/fj.14-263053

• allosteric modulation
• PPAR
• pharmacology
• drug discovery
• G protein-coupled receptor

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-a agonist fenofibrate exhibited submicromolar affinity for both receptors (pK(i)CB(1), 6.3 +/- 0.1; CB2, 7.7 +/- 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC(50), 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 [H-3]-CP55940 at the CB1 receptor, (k(fast) without: 1.2 +/- 0.2/min; with: 3.8 +/- 0.1 x 10(-2)/min) and decrease the maximal response to CP55940 (R-max, 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.

• 出版日期2015-4