Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors
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Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors. / Szymanska, Ewa; Frydenvang, Karla Andrea; Pickering, Darryl S; Krintel, Christian; Nielsen, Birgitte; Kooshki, Ayesheh; Zachariassen, Linda Grønborg; Olsen, Lars; Kastrup, Jette Sandholm Jensen; Johansen, Tommy Nørskov.
In: Journal of Medicinal Chemistry, Vol. 59, No. 1, 2016, p. 448-461.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors
AU - Szymanska, Ewa
AU - Frydenvang, Karla Andrea
AU - Pickering, Darryl S
AU - Krintel, Christian
AU - Nielsen, Birgitte
AU - Kooshki, Ayesheh
AU - Zachariassen, Linda Grønborg
AU - Olsen, Lars
AU - Kastrup, Jette Sandholm Jensen
AU - Johansen, Tommy Nørskov
PY - 2016
Y1 - 2016
N2 - A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1−3, at GluK1−3, and at native AMPA receptors. The individual enantiomers of two target compounds, (RS)-2-amino-3-(3,4-dichloro-5-(5-hydroxypyridin-3-yl)phenyl)- propanoic acid (37) and (RS)-2-amino-3-(3′-hydroxybiphenyl-3-yl)propanoic acid (38), were characterized. (S)-37 and (R)-38 were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with Kb of 1.80 and 3.90 μM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (S)-37 and (R)-38 showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (R)-38 having a binding mode not previously identified for amino acid-based antagonists.
AB - A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1−3, at GluK1−3, and at native AMPA receptors. The individual enantiomers of two target compounds, (RS)-2-amino-3-(3,4-dichloro-5-(5-hydroxypyridin-3-yl)phenyl)- propanoic acid (37) and (RS)-2-amino-3-(3′-hydroxybiphenyl-3-yl)propanoic acid (38), were characterized. (S)-37 and (R)-38 were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with Kb of 1.80 and 3.90 μM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (S)-37 and (R)-38 showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (R)-38 having a binding mode not previously identified for amino acid-based antagonists.
U2 - 10.1021/acs.jmedchem.5b01666
DO - 10.1021/acs.jmedchem.5b01666
M3 - Journal article
C2 - 26653877
VL - 59
SP - 448
EP - 461
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
ID: 152903964