title: 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 (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 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 × 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.
authors.affiliation: *School of Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom; and Neusentis-Pfizer Limited, Great Abington, Cambridge, United Kingdom.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Priestley
authors.affiliation: *School of Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom; and Neusentis-Pfizer Limited, Great Abington, Cambridge, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Nickolls
authors.affiliation: *School of Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom; and Neusentis-Pfizer Limited, Great Abington, Cambridge, United Kingdom.
authors.forename: Stephen P H
authors.initials: SP
authors.lastname: Alexander
authors.affiliation: *School of Life Sciences, University of Nottingham Medical School, Nottingham, United Kingdom; and Neusentis-Pfizer Limited, Great Abington, Cambridge, United Kingdom dave.kendall@nottingham.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D003412:Cricetulus; D003511:Cyclohexanols / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D047493:PPAR alpha / Q000819:agonists; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C571130:CNR1 protein, human; C588309:CNR2 protein, human; D003511:Cyclohexanols; D047493:PPAR alpha; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D011345:Fenofibrate
keywords: G protein-coupled receptor; PPAR; allosteric modulation; drug discovery; pharmacology