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

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

doi:10.1038/s41598-018-28263-7

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

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

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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.

Original language	English
Article number	10010
Journal	Scientific Reports
Volume	8
Issue number	1
Pages (from-to)	1-18
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-018-28263-7
Publication status	Published - 1 Dec 2018

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title = "Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1",

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.",

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T1 - Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

AU - Rexen Ulven, Elisabeth

AU - Trauelsen, Mette

AU - Brvar, Matjaz

AU - Lückmann, Michael

AU - Bielefeldt, Line Ø

AU - Jensen, Lisa K I

AU - Schwartz, Thue W

AU - Frimurer, Thomas M.

PY - 2018/12/1

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N2 - 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.

AB - 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.

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DO - 10.1038/s41598-018-28263-7

M3 - Journal article

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JO - Scientific Reports

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ER -

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

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