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Metabolic disorders

Safe cannabinoid receptor modulators in sight?

Nature Reviews Drug Discovery volume 11, page 749 (2012)Cite this article

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The endocannabinoids anandamide and 2-arachidonoylglycerol are lipid mediators that elicit a broad range of effects via G protein-coupled CB1Rs and CB2Rs. CB2Rs are found in the immune system and haematopoietic cells, whereas CB1Rs are most densely expressed in the central nervous system but are also located in the peripheral nervous system and peripheral organs. It is generally thought that the hyperphagic actions of endocannabinoids are mediated by CB1Rs located in the brain. However, recent studies have suggested that peripherally located CB1Rs are also likely to be involved. The authors therefore set out to explore the metabolic effects of specific modulation of peripheral CB1R.

To do this, they modified the structure of the CB1R inverse agonist SLV139 (ibipinabant), the development of which was discontinued in 2008, to reduce its brain penetrance. The resulting compound, JD5037, exhibited high affinity and specificity for peripheral CB1Rs, was unable to cross the blood–brain barrier in amounts sufficient to occupy CB1R in the brain, and had no effects on behaviour of mice.

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ORIGINAL RESEARCH PAPER

  1. Tam, J. et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 16, 167–179 (2012)

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  1. Sarah Crunkhorn
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Crunkhorn, S. Safe cannabinoid receptor modulators in sight?. Nat Rev Drug Discov 11, 749 (2012). https://doi.org/10.1038/nrd3851

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