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

Molecules

Elisabetta Panza¹  Orazio Taglialatela-Scafati¹  Giovanni Appendino²  FabioArturo Iannotti³  Luciano De Petrocellis³  Fabrizia De Maio³  Pietro Amodeo³  RosaMaria Vitale³ 

[1] Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, I-80131 Napoli, Italy;Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy;Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 80078 Pozzuoli (NA), Italy;

关键词: phytocannabinoids;    cannabimovone (cbm);    peroxisome proliferator-activated receptor gamma (pparγ);    molecular docking;    molecular dynamics;    insulin resistance;   

DOI  :  10.3390/molecules25051119

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown