3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors.
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.
Department of Chemistry, Biomolecular Sciences Building, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK.
Poh Wai
PW
Chia
Matthew R
MR
Livesey
Alexandra M Z
AM
Slawin
Tanja
T
van Mourik
David J A
DJ
Wyllie
David
D
O'Hagan
D018360:Crystallography, X-Ray; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C575596:3-fluoro-N-methyl-D-aspartic acid; D006845:Hydrocarbons, Fluorinated; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate