Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models

Wei Chen, Huoling Tang, Hongying Liu, Long Long, Zehui Gong, Jianquan Zheng, Mugen Chi, Yunde Xie, Zhibing Zheng, Song Li, Lili Wang
European Journal of Pharmacology 2010 July 10, 637 (1): 178-85
MJ15, a novel cannabinoid CB(1) receptor selective antagonist was discovered. In receptor binding assays, MJ15 displayed a high affinity for rat cannabinoid CB(1) receptor (K(i)=27.2 pM, and IC(50)=118.9 pM), but a much lower affinity for rat cannabinoid CB(2) receptor (only 46% inhibition at 10 microM). At the cellular level, the IC(50) values against activation of cannabinoid CB(1) and CB(2) receptors induced by Win55212-2 in specially designed EGFP-CB(1)_U2OS and EGFP-CB(2)_U2OS cells were 0.11 microM and >10 microM, respectively. In addition, MJ15 dose-dependently blocked Win55212-2 mediated increase of intracellular Ca(2+) levels in hippocampal cells and reversed the inhibitory effects of cannabinoid CB(1) receptor agonist on forskolin-stimulated adenylyl cyclase activity in CHO cells expressing the human cannabinoid CB(1) receptor. In animal experiments, MJ15 demonstrated remarkable effects from 20 to 40 mg/kg, including promoted the small intestine peristalsis in ICR mice and inhibited food intake and body weight increase in diet-induced obesity (DIO) rat and mouse. 40 mg/kg MJ15 significantly reduced food intake at initial 2 weeks of treatment, prevented the increase of body weight and adipose by 46% and 28% respectively in DIO rats, and reduced body weight and adipose gain by 70% and 23% respectively in early onset obesity DIO mice after 4 weeks treatment. Meanwhile, dyslipidemia were ameliorated in both models. Taken together the in vitro and in vivo data, MJ15 is demonstrated to be a potent and selective cannabinoid CB(1) receptor antagonist and holds a prominent potency in obesity and dyslipidemia treatment.

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