Identification and pharmacological characterization of succinate receptor agonists.
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.



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+]imobilization, 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.



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.



We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.|Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
Pierre
P
Geubelle
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.|Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
Julie
J
Gilissen
Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.|Laboratory of Molecular Modelling for (Bio)molecule Engineering, Institute of Chemistry and Biology of Membranes and Nano-objects, University of Bordeaux, Pessac, France.
Sébastien
S
Dilly
Laboratory of Experimental Surgery, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium.
Laurence
L
Poma
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
Nadine
N
Dupuis
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
Céline
C
Laschet
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
Dayana
D
Abboud
Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.|Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Japan.
Asuka
A
Inoue
Laboratory of Experimental Surgery, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium.
François
F
Jouret
Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
Bernard
B
Pirotte
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.|Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
Julien
J
Hanson
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D017433:Protein Structure, Secondary; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D019802:Succinic Acid / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human; D019802:Succinic Acid; D000242:Cyclic AMP