Identification and pharmacological characterization of succinate receptor agonists

[en] Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. Experimental Approach We screened a library of succinate analogues and analysed their activity on SUCNR1. In addition, we modelled a pharmacophore and a binding site for the 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 mobilisation, TGF-α shedding and recruitment of arrestin 3. The in vivo impact of SUCNR1 activation by these new agonists was evaluated on rat blood pressure. Key Results We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to the one of succinic acid. Interestingly, cis-epoxysuccinic acid was characterized by a 10 to 20 fold higher potency than succinate on the receptor. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM) as compared to succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all bioassays tested. In vivo, cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid increased rat blood pressure to the same extent as succinate did. Conclusions and Implications We provide new agonist tools for SUCNR1 that should facilitate further research on this understudied receptor.

Disciplines :

Biochemistry, biophysics & molecular biology
Pharmacy, pharmacology & toxicology

Author, co-author :

Geubelle, Pierre ; Université de Liège - ULiège > Form. doct. sc. biomed. & pharma. (paysage)

Gilissen, Julie

Dilly, Sebastien

POMA, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > Service de néphrologie

Dupuis, Nadine ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Laschet, Céline ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Abboud, Dayana ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Inoue, Asuka

Jouret, François ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques

Pirotte, Bernard ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Hanson, Julien ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Language :

English

Title :

Identification and pharmacological characterization of succinate receptor agonists

Publication date :

May 2017

Journal title :

British Journal of Pharmacology

ISSN :

0007-1188

Publisher :

Nature Publishing Group, London, United Kingdom

Volume :

174

Issue :

Pages :

796-808

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

http://onlinelibrary.wiley.com/doi/10.1111/bph.13738/full

Available on ORBi :

since 05 February 2017

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