- Identification and pharmacological characterization of succinate receptor agonists
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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, [Ca2+]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.
- Geubelle, Pierre,Gilissen, Julie,Dilly, Sébastien,Poma, Laurence,Dupuis, Nadine,Laschet, Céline,Abboud, Dayana,Inoue, Asuka,Jouret, Fran?ois,Pirotte, Bernard,Hanson, Julien
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supporting information
p. 796 - 808
(2017/04/14)
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- Process for preparing R-(-) -carnitine from S-(-)-chlorosuccinic acid or from a derivative thereof
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An inner salt of L-carnitine is prepared by reduction, with a suitable reducing agent, of a compound of formula (I): where X1and X2, which may be the same or different, are hydroxy, C1-C4alkoxy, phenoxy, halogen, or X1and X2, when taken together are an oxygen atom and the resulting compound is a derivative of succinic anhydride; Y is halogen, the mesyloxy or the tosyloxy group: and subsequent treatment with water, then with a base and then with trimethylamine.
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Page column 9
(2008/06/13)
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- Preparation of (S)-2-Substituted Succinates by Stereospecific Reductions of Fumarate and Derivatives with Resting Cells of Clostridium formicoaceticum
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Fumarate derivatives have been reduced to (S)-2-methylsuccinate 2a, (S)-2-ethylsuccinate 3a and (S)-2-chlorosuccinate 4a in up to 1 M concentrations with Clostridium formicoaceticum.Formate was the electron donor and viologens or anthraquinone-2,6-disulphonate acted as artificial electron mediators.Reductions with freeze-dried cells in 2H2O-buffers led to the (2R,3S)--dideuterated succinate derivatives.The productivity numbers ranged from 450 to 5000 and the enantiomeric excess of all (S)-2-substituted succinates was >/= 99percent.
- Eck, Richard,Simon, Helmut
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p. 13631 - 13640
(2007/10/02)
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- An efficient synthesis of enantiomerically pure (R)-(2-benzyloxyethyl)oxirane from (S)-aspartic acid
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A 3-step synthesis of the title compound from (S)-aspartic acid is described. The overall yield of this process is 65% and the enantiomeric purity (ep) of the product is greater than 99%.
- Frick,Klassen,Bathe,Abramson,Rapoport
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p. 621 - 623
(2007/10/02)
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- Application of (2)H N.M.R. Spectroscopy to Study the Incorporation of Enantiomeric -Labelled Putrescines into the Pyrrolizidine Alkaloid Retrorsine
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A sample of (2R)-putrescine (13) dihydrochloride was prepared from (2S)-aspartic acid (8), and (2S)-putrescine (15) dihydrochloride was synthesized from (2R)-aspartic acid.Feeding experiments carried out with these precursors on Senecio isatideus plants gave retrorsine (5) containing (2)H, and the distribution of (2)H from each experiment in retrorsine was determined by (2)H n.m.r. spectroscopy.All of the (2)H was confined to the base component of the alkaloid, retronecine (4).Retrorsine (14), derived biosynthetically from (2R)-putrescine (13) dihydrochloride was labelled with (2)H at C-2 and C-6α, while retrorsine (16), produced from (2S)-putrescine (15) dihydrochloride contained (2)H labels at C-6β and C-7α.These labelling patterns demonstrate that hydroxylation at C-7 of retronecine (4) proceeds with retention of configuration.In addition, the formation of the 1,2-double bond of retronecine involves removal of the pro-S hydrogen and retention of the pro-R hydrogen at the carbon atom which becomes C-2 of retronecine.
- Kunec, Ellen K.,Robins, David J.
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p. 1089 - 1094
(2007/10/02)
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- Preparation of Sephadex Derivatives with Optically Active Groups and Column-chromatographic Application to the Resolution of Some Cobalt(III) Complexes
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Optically active cation-exchangers were newly prepared as Sephadex derivatives derived from L-alanine, L-valine, L-aspartic acid, and L-threonine.They were applied to the column-chromatographic resolution of some cobalt(III) complexes, partial resolution being attained.
- Fujita, Miho,Sakano, Masanobu,Yoshikawa, Yuzo,Yamatera, Hideo
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p. 3211 - 3212
(2007/10/02)
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