title: Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents.
abstract: We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, United States.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shearman
authors.forename: D Sloan
authors.initials: DS
authors.lastname: Stribling
authors.forename: Ramon E
authors.initials: RE
authors.lastname: Camacho
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Rosko
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Guan
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Spann
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Macneil
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Mark T
authors.initials: MT
authors.lastname: Goulet
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Plummer
authors.forename: Paul E
authors.initials: PE
authors.lastname: Finke
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Shrenik K
authors.initials: SK
authors.lastname: Shah
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.forename: L H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: D Euan
authors.initials: DE
authors.lastname: Macintyre
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020372:Dexfenfluramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D004435:Eating / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists
chemical_list: C528030:5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide; D019440:Anti-Obesity Agents; D007093:Imidazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D020372:Dexfenfluramine