Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models.
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.
Chen
Wei
W
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Tang
Huoling
H
Liu
Hongying
H
Long
Long
L
Gong
Zehui
Z
Zheng
Jianquan
J
Chi
Mugen
M
Xie
Yunde
Y
Zheng
Zhibing
Z
Li
Song
S
Wang
Lili
L
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012377:Rodentia; D013997:Time Factors
C551906:5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(pyridin-3-methyl)-1H-pyrazole-3-carboxamide; D019440:Anti-Obesity Agents; D004041:Dietary Fats; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D000242:Cyclic AMP; D002118:Calcium