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Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity

Commerford, Susan, He, Xiaohui, Liu, Hong, Seidel, Martin, Jaton, Anne-Lise, Gromada, Jesper, Teixeira, Sandra, Gerber, Sarah, Chen, Alice, Dardik, Beatriz, Chaperon, Frederique, Schwartzkopf, Chad, Nguyen-Tran, Van, Hollenbeck, Thomas and Mcnamara, Peter (2011) Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 384 (6). pp. 565-581. ISSN 0028-1298


Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, Compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in Compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that Compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicates that Compound 64 possesses an antagonist activity in vivo. Dosed alone, Compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid-eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep Compound 64 was >3-fold less potent than for metabolic effects. Together these data suggested that 1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and 2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists, while maintaining metabolic efficacy. Furthermore, chronic treatment with Compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Cannabinoid receptor 1, obesity, REM sleep, body weight, plasma lipids
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Date Deposited: 28 Feb 2014 12:11
Last Modified: 28 Feb 2014 12:11


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