PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats

Br J Pharmacol. 2007 Nov;152(5):805-14. doi: 10.1038/sj.bjp.0707347. Epub 2007 Jun 25.


Background and purpose: Rimonabant (Acomplia, 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.

Experimental approach: A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTPgammaS, 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 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]-GTPgammaS 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.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Appetite Depressants / chemistry
  • Appetite Depressants / pharmacology*
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cyclic AMP / metabolism
  • Cyclohexanols / metabolism
  • Cyclohexanols / pharmacology
  • Dose-Response Relationship, Drug
  • Eating / drug effects*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Humans
  • Male
  • Molecular Structure
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Silicone Elastomers / pharmacology
  • Sulfur Radioisotopes
  • Weight Gain / drug effects


  • 1-(4-chlorophenyl)-3-(3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl)urea
  • Appetite Depressants
  • Cyclohexanols
  • Phenylurea Compounds
  • Piperidines
  • Pyrazoles
  • Pyridines
  • Receptor, Cannabinoid, CB1
  • Silicone Elastomers
  • Sulfur Radioisotopes
  • aminoethyl-aminopropyl-trimethoxysilane
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Cyclic AMP
  • Rimonabant