Determination of the absolute configuration of phosphinic analogues of glutamate

Bruno Commare; Delphine Rigault; Isabelle A. Lemasson; Patrick Deschamps; Alain Tomas; Pascal Roussel; Isabelle Brabet; Cyril Goudet; Jean-Philippe Pin; Frédéric R. Leroux; Françoise Colobert; Francine C. Acher

doi:10.1039/C4OB01960A

Determination of the absolute configuration of phosphinic analogues of glutamate†

Bruno Commare,‡^ab Delphine Rigault,‡^a Isabelle A. Lemasson,§^a Patrick Deschamps,^c Alain Tomas,^c Pascal Roussel,^d Isabelle Brabet,^ef Cyril Goudet,^ef Jean-Philippe Pin,^ef Frédéric R. Leroux,*^b Françoise Colobert*^b and Francine C. Acher*^a

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* Corresponding authors

^a Laboratoire de Chimie & Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601, Université Paris Descartes, Sorbonne Paris Cité, 45, rue des Saints-Pères 75270, Paris cedex 06, France
E-mail: francine.acher@parisdescartes.fr
Fax: +33 142 86 83 87
Tel: +33 142 86 33 21

^b Laboratoire de Chimie Moléculaire, UMR CNRS 7509, Université de Strasbourg, ECPM, 25, rue Becquerel 76087, Strasbourg, France
E-mail: francoise.colobert@unistra.fr, frederic.leroux@unistra.fr
Fax: +33 368 8527 42
Tel: +33 368 8527 46

^c Laboratoire de Cristallographie et RMN Biologiques, UMR CNRS 8015, Université Paris Descartes, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France
E-mail: patrick.deschamps@parisdescartes.fr, alain.tomas@parisdescartes.fr
Fax: +33 153 73 97 32
Tel: +33 153 73 98 40, +33 153 73 98 51

^d Unité de Catalyse et Chimie du solide, UMR CNRS 8012, École Nationale Supérieure de Chimie de Lille BP 90108-59652 Villeneuve d'Ascq cedex, France
E-mail: pascal.roussel@ensc-lille.fr
Fax: +33 320 43 68 14
Tel: +33 320 33 64 34

^e Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Université de Montpellier, F-34094 Montpellier, France
E-mail: cyril.goudet@igf.cnrs.fr
Fax: +33 467 54 24 32
Tel: +33 434 35 92 77

^f Inserm Unité 661, F-34094 Montpellier, France

Abstract

A series of phosphinic glutamate derivatives (e.g.LSP1-2111) have been proven to be potent agonists of metabotropic glutamate (mGlu) receptors and shown promising in vivo activity. However, so far all were synthesized and tested as a mixture of two diastereomers whose absolute and relative configurations are not known. In this study, the stereomers were separated on a Crownpack CR(+) column and their absolute configuration was assessed by means of a diastereoselective synthesis. Both separated L-stereomers activated the mGlu4 receptor with EC₅₀'s of 0.72 and 4.4 μM for (1S,1′S)-and (1S,1′R)-LSP1-2111, respectively.

Organic & Biomolecular Chemistry

Determination of the absolute configuration of phosphinic analogues of glutamate†

Abstract

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Determination of the absolute configuration of phosphinic analogues of glutamate

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