Dailey Kiersten A, Schneider Lillian N, Petreaca Ruben C, Yoder Ryan J
Biology program, The Ohio State University at Marion, Marion, Ohio, United States.
Molecular Genetics, Cancer Biolgoy, James Comprehensive Cancer Center, The Ohio State University at Marion, Marion, Ohio, United States.
MicroPubl Biol. 2025 Jul 24;2025. doi: 10.17912/micropub.biology.001690. eCollection 2025.
The targeting of the G-protein coupled receptor (GPCRs) glucagon-like-peptide-1-receptor (GLP-1R) by weight loss medications has become extremely prevalent due to the effectiveness of a class of GLP-1R agonists. Also, interest in cannabinoids, such as delta-9-tetrahydrocannabinol (THC), has risen independently of GLP's newfound fame due to the relaxation of legal hurdles across the nation to recreational cannabis usage. THC interacts with receptors in the endocannabinoid system, with the major ones being cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), both GPCRs. As these GPCR targets are becoming increasingly of interest due to these independent pathways, this study aimed to identify potential crossover between the endocannabinoid system and the GLP-1R system through molecular docking experiments. This was done using endogenous (2-AG and anandamide) and exogenous (THC) ligands of the endocannabinoid system , along with a proposed small oral agonist (danuglipron) of GLP-1R. Results indicated that danuglipron, a small GLP-1R agonist, had a higher binding affinity for CB1 and CB2 than any of the endogenous or exogenous ligands of the endocannabinoid system, suggesting the potential for cross-reactivity.
由于一类胰高血糖素样肽-1受体（GLP-1R）激动剂的有效性，减肥药物对G蛋白偶联受体（GPCRs）GLP-1R的靶向作用已变得极为普遍。此外，由于全国范围内对休闲大麻使用的法律限制有所放宽，大麻素（如δ-9-四氢大麻酚（THC））的关注度独立于GLP的新知名度而有所上升。THC与内源性大麻素系统中的受体相互作用，主要是大麻素受体1（CB1）和大麻素受体2（CB2），二者均为GPCRs。由于这些独立途径，这些GPCR靶点越来越受到关注，本研究旨在通过分子对接实验确定内源性大麻素系统与GLP-1R系统之间的潜在交叉。这是通过使用内源性大麻素系统的内源性（2-花生四烯酸甘油酯和花生四烯乙醇胺）和外源性（THC）配体，以及一种提议的GLP-1R口服小激动剂（达努格列净）来完成的。结果表明，一种小型GLP-1R激动剂达努格列净对CB1和CB2的结合亲和力高于内源性大麻素系统的任何内源性或外源性配体，表明存在交叉反应的可能性。
