PSNCBAM‐1, a novel allosteric antagonist at cannabinoid CB 1 receptors with hypophagic effects in rats

• Published in: British journal of pharmacology Vol. 152; no. 5; pp. 805 - 814
• Main Authors: Horswill, J G, Bali, U, Shaaban, S, Keily, J F, Jeevaratnam, P, Babbs, A J, Reynet, C, Wong Kai In, P
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707347

Background and purpose: Rimonabant (Acomplia TM , SR141716A), a cannabinoid CB 1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB 1 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 CB 1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM‐1, and its hypophagic effects in vivo . Experimental approach: A CB 1 yeast reporter assay was used as a primary screen. PSNCBAM‐1 was additionally characterized in [ 35 S]‐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 . Key results: In CB 1 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 [ 35 S]‐GTPγS binding and cAMP assays and was shown to be non‐competitive by Schild analyses. PSNCBAM‐1 did not affect CB 2 receptors. In radioligand binding assays, PSNCBAM‐1 increased the binding of [ 3 H]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 CB 1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB 1 receptor antagonist. British Journal of Pharmacology (2007) 152 , 805–814; doi: 10.1038/sj.bjp.0707347 ; published online 25 June 2007