5-(4-chlorophenyl)-1-(2-4-dichlorophenyl)-3-hexyl-1h-1-2-4-triazole and Weight-Gain

Peripheral blockade of cannabinoid CB(1) receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB(1) receptor antagonists. In this study we analysed the effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet-induced obesity.. To induce obesity, male Wistar rats were fed a high-fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg·kg(-1) LH-21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat-pad samples were analysed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether-à-go-go Related Gene (hERG) channels was evaluated.. LH-21 reduced feeding and body weight gain in HFD-fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD-1; (iii) CB(1) receptors; and (iv) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD- and SD-fed rats, LH-21 did not seem to induce hepatic, cardiac or renal toxicity.. These results support the hypothesis that treatment with the peripherally neutral acting CB(1) receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue.

Topics: Animals; Anti-Obesity Agents; Brain; Diet, High-Fat; Eating; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Gene Expression; HEK293 Cells; Humans; Intra-Abdominal Fat; Leptin; Lipogenesis; Liver; Male; Mice; Mice, Knockout; Obesity; PPAR alpha; PPAR gamma; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Triazoles; Weight Gain

LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [3H]CP55940 to cloned human and rat CB1 receptors with IC50 values of 631+/-98 nM, and 690+/-41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB1 receptor and does not act on the CB1 receptor to inhibit food intake in mice.

Topics: Animals; Anti-Obesity Agents; Binding, Competitive; Blood-Brain Barrier; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Cyclohexanols; Dose-Response Relationship, Drug; Drug Inverse Agonism; Eating; Humans; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Recombinant Proteins; Transfection; Triazoles; Weight Gain