PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB sub(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, In, PWK
• Format: Journal Article
• Language: English
• Published: 01-11-2007
• ISSN: 0007-1188
• DOI: 10.1038/sj.bjp.0707347

Background and purpose: Rimonabant (Acomplia, SR1 41716A), a cannabinoid CB sub(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 sub(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 sub(1) receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo. Experimental approach: A CB sub(1) yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [ super(35)S]-GTP gamma S, 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 sub(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 [ super(35)S]-GTP gamma S binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB sub(2) receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [ super(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 sub(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 sub(1) receptor antagonist.