Identification of the first succinate receptor agonists

Identification of the first succinate receptor agonists

 

The succinate receptor (formerly GPR91 or SUCNR1) is expressed in a variety of tissues, including blood cells, adipose tissue, the liver, retina, and kidney. Although its function remains to be established in most tissues, it has recently emerged as novel mediator in local stress situations, including in immune responses and inflammation, retinal angiogenesis and regulation of renin release.

Notwithstanding its implication in multiple (patho)physiological processes, the succinate receptor belongs to the category of attractive drug target whom the function has remained ill- defined due to unavailability of pharmacological tools.

Recently, researchers from the University of Liège (ULg) have discovered the first family of synthetic agonists, characterized for the best compound (namely cis-epoxysuccinic acid or cESA) with a 10 times higher potency compared to the natural ligand succinic acid. These tools led to the definition of a pharmacophore for agonistic activity on succinate receptors and a better understanding of its binding site. These highly potent and efficacious succinate receptor agonists have no activity on the mitochondrial SDH and can be used to specifically assess the impact of succinate receptor activation without interfering with the citric acid cycle.

The ULg’s researchers expect that the emergence of a properly characterized tool will open new possibilities for the characterization of succinate receptors and will pave the way to the development of highly selective and potent antagonists. Molecules with various pharmacological profiles are an absolute prerequisite to develop drug candidates and to validate the Succinate Receptor as an exploitable drug target in diseases with high level of unmet medical needs such as hypertension, retinal angiogenesis, inflammation and complications of diabetes mellitus or metabolic disease.

The results have been published in the British Journal of Pharmacology.

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