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. 2010 Oct;161(3):629-42.
doi: 10.1111/j.1476-5381.2010.00908.x.

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

N L Cluny  1 , V K Vemuri, A P Chambers, C L Limebeer, H Bedard, J T Wood, B Lutz, A Zimmer, L A Parker, A Makriyannis, K A Sharkey
Affiliations

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

N L Cluny et al. Br J Pharmacol. 2010 Oct.

Abstract

Background and purpose: Cannabinoid CB(1) receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.

Experimental approach: Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated.

Key results: AM6545 binds to CB(1) receptors with a K(i) of 1.7 nM and CB(2) receptors with a K(i) of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB(1) receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB(1) receptor gene-deficient mice, but not in CB(1)/CB(2) receptor double knockout mice.

Conclusions and implications: Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.

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Figures

Figure 1
Figure 1
Representative cAMP assay using hCB1-HEK293 cells for AM6545 (A) and AM251 (B). n = 3.
Figure 2
Figure 2
The effect of vehicle (4% DMSO, 1% Tween 80 in physiological saline), 10 mg·kg−1 or 20 mg·kg−1 AM6545 administered 1 h prior to vehicle, WIN55212-2 (1 mg·kg−1) or loperamide (1 mg·kg−1) on colonic propulsion in mice. Bars represent the mean ± s.e.mean, n = 6–7. **P < 0.01 and ***P < 0.001 denote a significant difference between groups analysed using one-way anova followed by Bonferroni's multiple comparisons post hoc test.
Figure 3
Figure 3
The effect of vehicle (2-HPBCD), AM6545 (8 mg·kg−1) or AM251 (8 mg·kg−1) on subsequent conditioned gaping (A) and positive hedonic reactions (B) elicited by 0.1% saccharin solution. The effect of AM6545 (10 mg·kg−1) on the consumption of flavoured food previously paired to vehicle, lithium chloride (LiCl, C) or 10 mg·kg−1 AM6545 (D) in naive rats. Bars represent the mean ± s.e.mean, n = 6–7. *P < 0.05, **P < 0.01 and ***P < 0.001 denote a significant difference from the vehicle control analysed using either one-way anova followed by Dunnett's post hoc test (A and B) or using paired t-test (C and D).
Figure 4
Figure 4
The effect of vehicle (4% DMSO, 1% Tween 80 in physiological saline) or AM6545 (5 or 10 mg·kg−1) on short-term food intake in rats (A). Bars represent the mean ± s.e.mean, n = 6–7. ***P < 0.001 denotes a significant difference to vehicle control analysed using one -way anova followed by Bonferroni's post hoc test. The effect of vehicle (4% DMSO, 1% Tween 80 in physiological saline) or AM6545 (10 mg·kg−1) on food intake (B) and weight change (C) in rats. Data points represent the mean ± s.e.mean, n = 4. *P < 0.05, **P < 0.01 and ***P < 0.001 denote a significant difference from vehicle control analysed using two-way mixed design anova with time as the repeated measure followed by Bonferroni's post hoc test.
Figure 5
Figure 5
The effect of vehicle (4% DMSO, 1% Tween 80 in physiological saline) or AM6545 (10 mg·kg−1) on food intake in vagotomized rats. Bars represent the mean ± s.e.mean, n = 5. *P < 0.05 and ***P < 0.001 denote a significant difference from vehicle control analysed using two-way mixed design anova with time as the repeated measure followed by Bonferroni's post hoc test.
Figure 6
Figure 6
The effect of vehicle (4% DMSO, 1% Tween 80 in physiological saline) or AM6545 (5 mg·kg−1) on food intake in control (wild-type or C57BL/6J), CB1 receptor knockout (CB1 KO) or CB1/CB2 receptor double knockout (CB1/CB2 KO) mice. Bars represent the mean ± s.e.mean, n = 5–14. **P < 0.01 and ***P < 0.001 denote a significant difference from vehicle control analysed using t-test.
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