Synthesis of phosphinic acids on the basis of hypophosphites: IV. Synthesis of pseudo-γ-glutamylglycine and its enantiomers

Ragulin, V. V.

doi:10.1007/s11176-005-0133-1

Cited by 6 publications

(2 citation statements)

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“…Searching for new mGlu4 receptor agonists, we carried out a virtual screening campaign and identified ( R )- 1 , named ( R )-PCEP, as the most potent and optimizable hit. Such pseudopeptides have been widely designed as enzyme inhibitors, among which are (±)- 1 and ( S )- 1 , , both previously synthesized and tested as part of a series of glutamine synthetase inhibitors. Indeed, 1 is a γ-glutamyl analogue that is derived from phosphinothricin (Chart ), a well-known inhibitor of that enzyme and used as a herbicide .…”

Section: Discussionmentioning

confidence: 99%

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A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

Selvam¹,

Oueslati²,

Lemasson³

et al. 2010

J. Med. Chem.

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(R)-PCEP (3-amino-3-carboxypropyl-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).

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