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3‐Fluoro‐ N ‐methyl‐ D ‐aspartic acid (3F‐NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA Receptors
Author(s) -
Chia Poh Wai,
Livesey Matthew R.,
Slawin Alexandra M. Z.,
van Mourik Tanja,
Wyllie David J. A.,
O'Hagan David
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200071
Subject(s) - nmda receptor , ionotropic effect , diastereomer , chemistry , agonist , stereochemistry , stereoselectivity , stereocenter , glutamate receptor , receptor , biochemistry , enantioselective synthesis , catalysis
N ‐Methyl‐ D ‐aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a CF bond at the 3‐position of ( S )‐NMDA generates either the (2 S, 3 S )‐ or (2 S, 3 R )‐ 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 (2 S, 3 R )‐diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the CF bond (2 S, 3 S )‐3F‐NMDA to adopt a gauche conformation to the CN + bond in the binding conformation, whereas the (2 S, 3 R )‐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.