Studies on an (<i>S</i>)‑2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

Abstract

IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (<i>R</i>)-2-amino-2-(4-methoxyphenyl)­ethanol as a chiral auxiliary, (2<i>R</i>)-IKM-159 and the (2<i>S</i>)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2<i>R</i>)-IKM-159, whereas the (2<i>S</i>)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2<i>R</i>)-IKM-159 at the glutamate binding site. (2<i>R</i>)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors