Identification and pharmacological characterization of succinate receptor agonists

  • Br J Pharmacol. 2017 May;174(9):796-808. doi: 10.1111/bph.13738.
Pierre Geubelle  1  2 ,  Julie Gilissen  1  2 ,  Sébastien Dilly  2  3 ,  Laurence Poma  4 ,  Nadine Dupuis  1 ,  Céline Laschet  1 ,  Dayana Abboud  1 ,  Asuka Inoue  5  6 ,  François Jouret  4 ,  Bernard Pirotte  2 ,  Julien Hanson  1  2
Affiliations
  • 1. Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
  • 2. Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
  • 3. Laboratory of Molecular Modelling for (Bio)molecule Engineering, Institute of Chemistry and Biology of Membranes and Nano-objects, University of Bordeaux, Pessac, France.
  • 4. Laboratory of Experimental Surgery, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium.
  • 5. Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.
  • 6. Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Japan.
PMID: 28160606 DOI: 10.1111/bph.13738
Abstract

Background and purpose: The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of succinate receptors has remained ill-defined because no pharmacological tools were available. We report on the discovery of the first family of potent synthetic agonists.

Experimental approach: We screened a library of succinate analogues and analysed their activity on succinate receptors. Also, we modelled a pharmacophore and a binding site for this receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [CA2+ ]i mobilization, TGF-α shedding and recruitment of Arrestin 3. The in vivo effects of activating succinate receptors with these new agonists was evaluated on rat BP.

Key results: We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to that of succinic acid. Interestingly, cis-epoxysuccinic acid was 10- to 20-fold more potent than succinic acid on succinate receptors. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM), compared with succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all in vitro assays. Both cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid were as potent as succinate in increasing rat BP.

Conclusions and implications: We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.

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