Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

Elisabeth Rexen Ulven,Mette Trauelsen,Line Ø Bielefeldt,Thue W Schwartz,Michael Lückmann,Matjaz Brvar,Lisa K I Jensen,Thomas M Frimurer

doi:10.1038/s41598-018-28263-7

Elisabeth Rexen Ulven, Mette Trauelsen + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-28263-7

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Abstract

The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

Highlights

The 7-transmembrane G-protein coupled receptor succinate receptor 1 (SUCNR1) was first identified in 2001 and found to have close homology with the purinergic receptor P2Y1
Coupling of 2 to various carboxylic acids was efficiently achieved via the corresponding acyl fluoride generated in situ by fluoro-N,N,N’,N’-bis(tetramethylene)foramidinium hexafluorophosphate (BTFFH)[12]
We here report the structure-activity investigations of a series of non-metabolite SUCNR1 agonists that was originally identified from a computational, receptor-structure derived agonistic lead

Summary

Introduction

The 7-transmembrane G-protein coupled receptor SUCNR1 was first identified in 2001 and found to have close homology with the purinergic receptor P2Y1. In 2004, SUCNR1 was deorphanised and found to be activated by the citric acid cycle intermediate succinate at micromolar concentrations[2]. The other citric acid cycle intermediates oxaloacetate and α-ketoglutarate were found to activate the receptor, albeit with reduced potency[3,4]. Most studies so far indicate that antagonists for SUCNR1 might be optimal from a therapeutic perspective this has yet to be experimentally confirmed and is mainly based on studies using the natural agonist succinate, a compound that beside its relatively weak potency is an intermediate in the citric acid cycle and exerts effects unrelated to SUCNR1. We report the further development and structure-activity investigations of this agonist series. All compounds have been studied on both the human and mouse orthologues in order to develop tool compounds for further investigations of SUCNR1

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