Current address: OSI Pharmaceuticals Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. Prosidion Limited is a wholly owned subsidiary of OSI Pharmaceuticals Inc.
PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats
Version of Record online: 29 JAN 2009
2007 British Pharmacological Society
British Journal of Pharmacology
Special Issue: Special Issue: Cannabinoid Pharmacology
Volume 152, Issue 5, pages 805–814, November 2007
How to Cite
Horswill, J. G., Bali, U., Shaaban, S., Keily, J. F., Jeevaratnam, P., Babbs, A. J., Reynet, C. and Wong Kai In, P. (2007), PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. British Journal of Pharmacology, 152: 805–814. doi: 10.1038/sj.bjp.0707347
- Issue online: 29 JAN 2009
- Version of Record online: 29 JAN 2009
- (Received March 7, 2007, Revised April 25, 2007, Accepted May 3, 2007)
- allosteric modulator;
- cannabinoid receptor;
Background and purpose:
Rimonabant (AcompliaTM, SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo.
A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTPγS, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo.
In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [35S]-GTPγS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [3H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight.
Conclusions and implications:
PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.
British Journal of Pharmacology (2007) 152, 805–814; doi:10.1038/sj.bjp.0707347; published online 25 June 2007