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

Abstract

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.

• Authors: J G Horswill, U Bali, S Shaaban, J F Keily, P Jeevaratnam, A J Babbs, C Reynet, P Wong Kai In
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 5 Pg. 805-14 (Nov 2007) ISSN: 0007-1188 [Print] England
• PMID: 17592509 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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