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Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents.
Eur J Pharmacol. 2008 Jan 28; 579(1-3):215-24.EJ

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+Show Affiliations

Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, United States.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

18021763

Citation

Shearman, Lauren P., et al. "Characterization of a Novel and Selective Cannabinoid CB1 Receptor Inverse Agonist, Imidazole 24b, in Rodents." European Journal of Pharmacology, vol. 579, no. 1-3, 2008, pp. 215-24.
Shearman LP, Stribling DS, Camacho RE, et al. Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents. Eur J Pharmacol. 2008;579(1-3):215-24.
Shearman, L. P., Stribling, D. S., Camacho, R. E., Rosko, K. M., Wang, J., Tong, S., Feng, Y., Marsh, D. J., Yu, H., Guan, X., Spann, S. K., Macneil, D. J., Fong, T. M., Metzger, J. M., Goulet, M. T., Hagmann, W. K., Plummer, C. W., Finke, P. E., Mills, S. G., ... Strack, A. M. (2008). Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents. European Journal of Pharmacology, 579(1-3), 215-24.
Shearman LP, et al. Characterization of a Novel and Selective Cannabinoid CB1 Receptor Inverse Agonist, Imidazole 24b, in Rodents. Eur J Pharmacol. 2008 Jan 28;579(1-3):215-24. PubMed PMID: 18021763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents. AU - Shearman,Lauren P, AU - Stribling,D Sloan, AU - Camacho,Ramon E, AU - Rosko,Kimberly M, AU - Wang,Junying, AU - Tong,Sharon, AU - Feng,Yue, AU - Marsh,Donald J, AU - Yu,Hong, AU - Guan,Xiaoming, AU - Spann,Stephanie K, AU - Macneil,Douglas J, AU - Fong,Tung M, AU - Metzger,Joseph M, AU - Goulet,Mark T, AU - Hagmann,William K, AU - Plummer,Christopher W, AU - Finke,Paul E, AU - Mills,Sander G, AU - Shah,Shrenik K, AU - Truong,Quang, AU - Van der Ploeg,L H T, AU - Macintyre,D Euan, AU - Strack,Alison M, Y1 - 2007/10/25/ PY - 2007/01/03/received PY - 2007/09/11/revised PY - 2007/10/16/accepted PY - 2007/11/21/pubmed PY - 2008/4/16/medline PY - 2007/11/21/entrez SP - 215 EP - 24 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 579 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18021763/Characterization_of_a_novel_and_selective_cannabinoid_CB1_receptor_inverse_agonist_Imidazole_24b_in_rodents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)01195-8 DB - PRIME DP - Unbound Medicine ER -