Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

Abstract

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.

The Endocannabinoid System and PPARs: Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation

“…In this regard, it has been demonstrated that synthetic and plant-derived cannabinoids attenuate neuroinflammation and neurodegeneration in animal models of acute or chronic neurodegenerative disorders through activation of cannabinoid receptors and PPARγ pathway [ 81 , 82 , 83 , 84 ]. While natural and synthetic phytocannabinoids including Δ 9 -tetrahydrocannabinol (Δ 9 -THC), Cannabidiol (CBD), Δ9-THC acid, ajulemic acid, quinone derivatives [ 85 , 86 , 87 , 88 , 89 ], and the recently identified cannabimovone [ 90 ] are PPARγ agonists, the acidic derivatives cannabigerolic and cannabidiolic acids exhibit a dual agonist profile [ 91 ] ( Figure 4 ). The endocannabinoid anandamide (AEA) activates both PPARα [ 92 ] and PPARγ [ 93 ], albeit its efficacy and potency toward PPARα are higher in comparison to PPARγ.…”

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors

“…A 60 Å × 60 Å × 70 Å grid, centred in the orthosteric binding pocket, was generated with the program AutoGrid 4.2 included in Autodock 4.2 distribution, with a spacing of 0.375 Å. Docking runs were carried out by either keeping fixed the whole protein or alternately allowing the rotation of triples of selected residues (Asp114/Glu206/Trp402 for both histamine and PEA-OXA, Tyr374/Tyr394/Phe398 and Tyr374/Thr375/Ser203 for pea-oxa alone). 100 molecular AutoDock docking runs for each docking calculation were performed adopting a Lamarckian Genetic Algorithm (LGA) and protocol already published [ 38 ]. Flexibility was used for all rotatable bonds of both docked ligands.…”

Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists

“…Grids for docking evaluation with a spacing of 0.375 Å and 60 × 60 × 60 points, centered on the ligand-binding site, were generated using the program AutoGrid (version 4.2) included in Autodock (version 4.2) distribution. 100 molecular docking runs for each docking calculation were performed adopting a Lamarckian Genetic Algorithm (LGA) and the protocol already published [ 60 ]. Flexibility was used for all rotatable bonds of the docked ligands.…”

“…To perform MD simulations in solvent, the complexes were confined in TIP3P water periodic truncated octahedron boxes exhibiting a minimum distance between solute atoms and box surfaces of 10 Å, using the leap module of the AmberTools16 package (version 16). MD simulations were performed using a protocol published elsewhere [ 60 ]. The cpptraj module of AmberTools16 and program UCSF Chimera v1.10.1 [ 62 ] were used to perform MD analysis and to draw the figures, respectively.…”