Identification of Novel Cannabinoid CB2 Receptor Agonists from Botanical Compounds and Preliminary Evaluation of Their Anti-Osteoporotic Effects

Abstract

As cannabinoid CB2 receptors (CB2R) possess various pharmacological effects—including anti-epilepsy, analgesia, anti-inflammation, anti-fibrosis, and regulation of bone metabolism—without the psychoactive side effects induced by cannabinoid CB1R activation, they have become the focus of research and development of new target drugs in recent years. The present study was intended to (1) establish a double luciferase screening system for a CB2R modulator; (2) validate the agonistic activities of the screened compounds on CB2R by determining cAMP accumulation using HEK293 cells that are stably expressing CB2R; (3) predict the binding affinity between ligands and CB2 receptors and characterize the binding modes using molecular docking; (4) analyze the CB2 receptors–ligand complex stability, conformational behavior, and interaction using molecular dynamics; and (5) evaluate the regulatory effects of the screened compounds on bone metabolism in osteoblasts and osteoclasts. The results demonstrated that the screening system had good stability and was able to screen cannabinoid CB2R modulators from botanical compounds. Altogether, nine CB2R agonists were identified by screening from 69 botanical compounds, and these CB2R agonists exhibited remarkable inhibitory effects on cAMP accumulation and good affinity to CB2R, as evidenced by the molecular docking and molecular dynamics. Five of the nine CB2R agonists could stimulate osteoblastic bone formation and inhibit osteoclastic bone resorption. All these findings may provide useful clues for the development of novel anti-osteoporotic drugs and help elucidate the mechanism underlying the biological activities of CB2R agonists identified from the botanical materials.

Cannabidiol Inhibits Inflammation Induced by Cutibacterium acnes-Derived Extracellular Vesicles via Activation of CB2 Receptor in Keratinocytes

“… 35 On the other hand, studies have shown that TPRV1 activation caused release of inflammatory cytokines, while CB2 receptor activation prevented local and systemic immune response. 36 , 37 These earlier studies prompted us to focus on the roles of CB2 receptor and TRPV1 in the anti-inflammatory action of CBD. In our study, the expression of CB2 receptor and TRPV1 in keratinocytes was confirmed and the effects of antagonists of the two receptors were studied.…”

Evaluation of Biological Mechanisms of Quanduzhong Capsule for Treating Osteoporosis by Integrating Untargeted Metabolomics and Network Pharmacology

“…Targets were collected from DrugBank (n ¼ 235), Genecards (n ¼ 1,173), OMIM (n ¼ 11), PharmGKB (n ¼ 12), and TTD (n ¼ 30); the reference targets were investigated in Pubmed, including CNR2, EFNB2, EPHB4, ITGB1, NFE2L2, GSK3B, FOXF2, SIRT3, TSC1, BHLHE40, GSTM1, and TFRCU. [19][20][21][22][23][24][25][26][27][28][29] We identified 1,374 targets related to OP after deleting duplicates. We searched for the 85 DZ targets checked by UNIFI from ETCM, HERB, and SwissTargetPrediction.…”

Network Pharmacology, Molecular Docking, and Molecular Dynamic-Based Investigation on the Mechanism of Compound Chrysanthemum in the Treatment of Asthenopia

“…Firstly, minimizing the target protein free energy with Chem3D, the target proteins were introduced into AutoDock-Tools (Version: 1.5.7), where water molecules and original ligands in the target proteins were removed, and hydrogen atoms were added, then docking box generation within 40 Å with the original ligand as the center. The active ingredients that can bind to these targets were used as ligands, and the 3D molecular conformations of the ingredients were then obtained from the PubChem Compound database [43]. Subsequently, the docking experiments were achieved with the help of AutoDock Vina in a semiflexible 2.2.6.…”