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Expert Opin Investig Drugs. 2012 Sep;21(9):1309-22. doi: 10.1517/13543784.2012.704019. Epub 2012 Jul 11.

Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders.

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  • 1Institute of Biomolecular Chemistry - CNR, Endocannabinoid Research Group, Pozzuoli (NA), Italy.



Excessive abdominal obesity along with other risk factors results in the metabolic syndrome, which can lead to heart disease, Type-2 diabetes, and death. The endocannabinoid system (ECS) is composed of neutral lipids which signal through the G-protein coupled cannabinoid receptors CB1 and CB2. In abdominal obesity, the ECS is generally up-regulated in central and peripheral tissues and its blockade results in positive metabolic changes. Rimonabant (SR141716) was the first selective CB1 inverse agonist/antagonist marketed for the treatment of obesity; however, psychiatric side effects, which may result from its actions in the brain or its inverse agonism, resulted in its removal from the market. Recently, key metabolic-modulatory roles for the ECS within peripheral tissues have come to light. Thus there has been significant effort put forth by several laboratories to develop either neutral or peripherally restricted CB1 antagonists.


In this review we shall provide an overview of the roles the ECS plays outside the brain in regulating metabolism, and highlight the latest advances in the development of neutral and/or peripherally restricted CB1 antagonists, and other state of the art strategies that minimize endocannabinoid overactivity.


The CB1 receptor is potentially a clinically relevant target for the design of therapies against metabolic syndrome, deserving the development and clinical testing of CB1-neutral antagonists which can pass the blood - brain barrier or of peripherally restricted inverse agonists/neutral antagonists. Furthermore, reducing endocannabinoid biosynthesis could represent an alternative strategy to counteract peripheral endocannabinoid overactivity through dietary n-3 polyunsaturated fatty acids or the development of diacylglycerol lipase inhibitors.

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