3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA Receptors

Poh Wai Chia, Matthew R. Livesey, Alexandra Martha Zoya Slawin, Tanja van Mourik, David J. A. Wyllie, David O'Hagan

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

N-Methyl-D-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C?F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepared by synthesis in enantiomerically pure forms and it was found that (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C?F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C?N+ bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilisation, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the molecular conformation of beta-fluorinated amino acids and thus probing the active conformations of bioactive compounds at receptors.

Original languageEnglish
Pages (from-to)8813-8819
Number of pages7
JournalChemistry - A European Journal
Volume18
Issue number28
DOIs
Publication statusPublished - 9 Jul 2012

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