HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/R2185    most recent 00663.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Chambers, A. P. Articles by Sharkey, K. A. Search for Related Content PubMed PubMed Citation Articles by Chambers, A. P. Articles by Sharkey, K. A.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

A neutral CB₁ receptor antagonist reduces weight gain in rat

¹Hotchkiss Brain Institute and Institute of Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada; ²Center for Drug Discovery, Northeastern University, Boston, Massachusetts

Submitted 12 September 2007 ; accepted in final form 18 October 2007

Cannabinoid (CB)₁ receptor inverse agonists inhibit food intake in animals and humans but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB₁ antagonist, AM4113, on food intake, weight gain, and emesis. Neutral antagonist and binding properties were confirmed in HEK-293 cells transfected with human CB₁ or CB₂ receptors. AM4113 had no effect on forskolin-stimulated cAMP production at concentrations up to 630 nM. The K_i value of AM4113 (0.80 ± 0.44 nM) in competitive binding assays with the CB_1/2 agonist [³H]CP55,940 was 100-fold more selective for CB₁ over CB₂ receptors. We determined that AM4113 antagonized CB₁ receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0–20 mg/kg) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg/kg), a highly anorectic dose of AM4113 (10 mg/kg) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB₁ receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans, they could be developed into a new class of antiobesity agents.

cannabinoid receptor; food intake; inverse agonist; obesity; emesis; hypothermia

This article has been cited by other articles:

				G. Kunos and D. Osei-Hyiaman Endocannabinoids and Liver Disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1101 - G1104. [Abstract] [Full Text] [PDF]