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
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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. / Juknaite, Lina; Sugamata, Yutaro; Tokiwa, Kazuya; Ishikawa, Yuichi; Takamizawa, Satoshi; Eng, Andrew; Sakai, Ryuichi; Pickering, Darryl S; Frydenvang, Karla; Swanson, Geoffrey T; Kastrup, Jette Sandholm Jensen; Oikawa, Masato.
In: Journal of Medicinal Chemistry, Vol. 56, No. 6, 2013, p. 2283-2293.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159
T2 - asymmetric synthesis, neuroactivity, and structural characterization
AU - Juknaite, Lina
AU - Sugamata, Yutaro
AU - Tokiwa, Kazuya
AU - Ishikawa, Yuichi
AU - Takamizawa, Satoshi
AU - Eng, Andrew
AU - Sakai, Ryuichi
AU - Pickering, Darryl S
AU - Frydenvang, Karla
AU - Swanson, Geoffrey T
AU - Kastrup, Jette Sandholm Jensen
AU - Oikawa, Masato
PY - 2013
Y1 - 2013
N2 - IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogs 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. Employing (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 total 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.
AB - IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogs 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. Employing (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 total 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.
U2 - 10.1021/jm301590z
DO - 10.1021/jm301590z
M3 - Journal article
C2 - 23432124
VL - 56
SP - 2283
EP - 2293
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 6
ER -
ID: 44730110