title: Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.
abstract: 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.
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. richard_z_chen@merck.com
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Frassetto
authors.forename: Julie Z
authors.initials: JZ
authors.lastname: Lao
authors.forename: Ruey-Ruey C
authors.initials: RR
authors.lastname: Huang
authors.forename: Jing C
authors.initials: JC
authors.lastname: Xiao
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clements
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Walsh
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D004435:Eating / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C515162:5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole; D019440:Anti-Obesity Agents; D003511:Cyclohexanols; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; D014230:Triazoles; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP