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-a agonist fenofibrate exhibited submicromolar affinity for both receptors (pK i CB 1 , 6.3 6 0.1; CB 2 , 7.7 6 0.1). Functionally, fenofibrate acted as an agonist at the CB 2 receptor (pEC 50 , 7.7 6 0.1) and a partial agonist at the CB 1 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 6 0.2/min; with: 3.8 6 0.1 3 10 22 /min) and decrease the maximal response to CP55940 (R max , 86 6 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 6 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.

Antidepressant‐like effects of fenofibrate in mice via the hippocampal brain‐derived neurotrophic factor signalling pathway

“…Recently, Nickolls et al () found that fenofibrate also acts as an agonist of the CB 2 receptor and a partial agonist of the CB 1 receptor. It has been demonstrated that chronic stress leads to widespread reductions in anandamide concentrations throughout the brain, together with decreased CB 1 receptor signal transduction in subcortical structures, such as the hippocampus, while the direct pharmacological activation of the CB 1 receptor produces antidepressant‐like responses in the FST (Hill et al, , , ; Jiang et al, ; Bambico et al, ).…”

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

“…8 These include CB1 receptor NAMs such as PSNCBAM-1 ( 2 ) 9 , fenofibrate ( 3 ), 10 and CB1 receptor PAMs ZCZ011 ( 4 ) 11 and GAT211 ( 5 ) 12 (Fig. 1).…”

Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)

“…29 The dopamine transport inhibitor RTI-371 33 and the PPAR-α agonist fenofibrate have also been suggested to act at a CB1R allosteric site. 34 Very recently, we have shown that cannabidiol, the nonpsychoactive constituent of Cannabis sativa , exhibits negative allosteric modulation at CB1R. 35 Additionally, ligands displaying positive allosteric modulation of orthosteric ligand’s binding and function have been reported recently.…”