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

Abstract

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 (CB 1) or cannabinoid type 2 (CB 2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-α agonist fenofibrate exhibited submicromolar affinity for both receptors (pK i CB 1, 6.3 ± 0.1; CB 2, 7.7 ± 0.1). Functionally, fenofibrate acted as an agonist at the CB 2 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 [ 3 H]-CP55940 at the CB 1 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 CB 1 receptors (pEC 50, 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.