Canna~Fangled Abstracts

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

By December 30, 2014 No Comments
2014 Dec 30. pii: fj.14-263053. [Epub ahead of print]

pm1A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.


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-α 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 CB1receptor, 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 [3H]-CP55940 at the CB1 receptor, (kfastwithout: 1.2 ± 0.2/min; with: 3.8 ± 0.1 × 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 CB1receptors (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.-Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., Kendall, D. A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.


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


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