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.
Subject(s)
Appetite Depressants/pharmacology , Eating/drug effects , Phenylurea Compounds/pharmacology , Pyridines/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Allosteric Regulation/drug effects , Animals , Appetite Depressants/chemistry , 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 , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Humans , Male , Molecular Structure , Phenylurea Compounds/chemistry , Piperidines/pharmacology , Pyrazoles/pharmacology , Pyridines/chemistry , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/metabolism , Rimonabant , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Silicone Elastomers/pharmacology , Sulfur Radioisotopes , Weight Gain/drug effectsABSTRACT
A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.
