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

• Published in: Chemistry : a European journal 2012-07, Vol.18 (28), p.8813-8819
• Main Authors: Chia, Poh Wai, Livesey, Matthew R., Slawin, Alexandra M. Z., van Mourik, Tanja, Wyllie, David J. A., O'Hagan, David
• Format: Article
• Language: English
• Subjects: Amino acids; Binding; Biocompatibility; Bonding; Chemistry; Crystallography, X-Ray; fluorine; glutamate receptors; Glutamates; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - chemistry; Molecular Conformation; Molecular Structure; N-Methylaspartate - analogs & derivatives; N-Methylaspartate - chemical synthesis; N-Methylaspartate - chemistry; neurotransmitters; NMDA; Receptors; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - chemistry; Stereoisomerism; Structure-Activity Relationship; Synthesis; Utilities
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201200071

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. Two stereoisomeric analogues of the glutamate receptor agonist N‐methyl‐D‐aspartate (NMDA), display very different activities as a result of the diastereotopic replacement of each of the C‐3 hydrogens for fluorine. The difference in agonist activity is attributed to the CF bond inducing a different conformational bias in each case. The study illustrates the power of using the CF bond to influence the conformation of bioactive amines and explore preferred binding modes to large protein receptors.