Identification and pharmacological characterization of succinate receptor agonists. (10th March 2017)

• Record Type: Journal Article
• Authors: Geubelle, Pierre; Gilissen, Julie; Dilly, Sébastien; Poma, Laurence; Dupuis, Nadine; Laschet, Céline; Abboud, Dayana; Inoue, Asuka; Jouret, François; Pirotte, Bernard; Hanson, Julien
• Is Part Of: British journal of pharmacology. Volume 174:Number 9(2017)
• Page Start: 796
• Page End: 808
• Publication Date: 2017-03-10
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.13738
• Languages: English
• ISSNs: 0007-1188

Abstract

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, [Ca 2+ ]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.