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 M Z Slawin, Tanja van Mourik, David J A Wyllie, David O'Hagan

Research output: Contribution to journalArticlepeer-review

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 β-fluorinated amino acids and thus probing the active conformations of bioactive compounds at receptors.
Original languageEnglish
Pages (from-to)8813-9
Number of pages7
JournalChemistry - A European Journal
Volume18
Issue number28
DOIs
Publication statusPublished - Jul 2012

Keywords

  • fluorine
  • glutamate receptors
  • molecular conformation
  • neurotransmitters
  • NMDA

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