title: Studies on an (S)-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 (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-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 (2R)-IKM-159, whereas the (2S)-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 (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.
authors: Graduate School of Nanobioscience, Yokohama City University , Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.
authors: Lina
authors: L
authors: Juknaitė
authors: Yutaro
authors: Y
authors: Sugamata
authors: Kazuya
authors: K
authors: Tokiwa
authors: Yuichi
authors: Y
authors: Ishikawa
authors: Satoshi
authors: S
authors: Takamizawa
authors: Andrew
authors: A
authors: Eng
authors: Ryuichi
authors: R
authors: Sakai
authors: Darryl S
authors: DS
authors: Pickering
authors: Karla
authors: K
authors: Frydenvang
authors: Geoffrey T
authors: GT
authors: Swanson
authors: Jette S
authors: JS
authors: Kastrup
authors: Masato
authors: M
authors: Oikawa
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D007536:Isomerism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001572:Benzofurans; C552887:IKM 159; D008024:Ligands; D011760:Pyrrolidinones; D018091:Receptors, AMPA