617-41-4Relevant articles and documents
Identification and pharmacological characterization of succinate receptor agonists
Geubelle, Pierre,Gilissen, Julie,Dilly, Sébastien,Poma, Laurence,Dupuis, Nadine,Laschet, Céline,Abboud, Dayana,Inoue, Asuka,Jouret, Fran?ois,Pirotte, Bernard,Hanson, Julien
supporting information, p. 796 - 808 (2017/04/14)
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.
Accessing Centnerszwer's quasiracemate-molecular shape controlled molecular recognition
Spaniol, Jacqueline M.,Wheeler, Kraig A.
, p. 64921 - 64929 (2016/07/21)
M. Centnerszwer's seminal 1899 report investigated the stereochemical relationship between optical antipodes of different substances using melting-point behavior. One intriguing melting-point phase diagram produced from this early investigation combined (+)-2-chlorosuccinic acid [(+)-1] and (-)-2-bromosuccinic acid [(-)-2]. While Centnerszwer's data clearly indicates the formation of a quasiracemic phase-i.e., materials constructed from pairs of isosteric molecules of opposite handedness-at the 1:1 component ratio, this material is energetically less favorable than the chiral counterparts. The consequence of this crystal instability is significant as evident by the absence of literature sited crystal structures for the quasiracemic phase (+)-1/(-)-2 and racemates (±)-1 and (±)-2. This study circumvented this challenge by generating multi-molecular assemblies using additional crystallizing agents capable of complementing the hydrogen-bond abilities of succinic acids 1 and 2. Both imidazole (Im) and 4,4′-bipyridyl-N,N′-dioxide (BPDO) served as tailor-made additives that effectively modified the crystal packing landscape of quasiracemate of (+)-1/(-)-2. Combining imidazole with the quasiracemate, racemate, and enantiopure forms of 1 and 2 resulted in crystal structures characterized as molecular salts with layered motifs formed from highly directional N+-H?carboxylate and carboxyl?carboxylate interactions. In contrast to the enantiopure [(+)-1·Im and (-)-2·Im] and racemic [(±)-1·Im and (±)-2·Im] systems, neighboring molecular layers observed in quasiracemate (+)-1/(-)-2·Im are organized by approximate inversion symmetry. Assessment of the crystal packing efficiency for this series of molecular salts via crystal densities and packing coefficients (Ck) indicates imidazole greatly alters the crystal landscape of the system in favor of racemic and quasiracemic crystal packing. A similar desymmetrized crystal environment was also realized for the ternary cocrystalline system of (+)-1/(-)-2·BPDO where the components organize via N+-O-?carboxyl contacts. This study underscores the importance of molecular shape to molecular recognition processes and the stabilizing effect of tailor-made additives for creating new crystalline phases of previously inaccessible crystalline materials.
Preparation of (S)-2-Substituted Succinates by Stereospecific Reductions of Fumarate and Derivatives with Resting Cells of Clostridium formicoaceticum
Eck, Richard,Simon, Helmut
, p. 13631 - 13640 (2007/10/02)
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.
