Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors

Ewa Szymanska; Karla Andrea Frydenvang; Darryl S Pickering; Christian Krintel; Birgitte Nielsen; Ayesheh Kooshki; Linda Grønborg Zachariassen; Lars Olsen; Jette Sandholm Jensen Kastrup; Tommy Nørskov Johansen

doi:10.1021/acs.jmedchem.5b01666

Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors

Ewa Szymanska, Karla Andrea Frydenvang, Darryl S Pickering, Christian Krintel, Birgitte Nielsen, Ayesheh Kooshki, Linda Grønborg Zachariassen, Lars Olsen, Jette Sandholm Jensen Kastrup, Tommy Nørskov Johansen

5 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	1
Pages (from-to)	448-461
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01666
Publication status	Published - 14 Jan 2016

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Szymanska, E., Frydenvang, K. A., Pickering, D. S., Krintel, C., Nielsen, B., Kooshki, A., Zachariassen, L. G., Olsen, L., Kastrup, J. S. J., & Johansen, T. N. (2016). Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors. Journal of Medicinal Chemistry, 59(1), 448-461. https://doi.org/10.1021/acs.jmedchem.5b01666

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title = "Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors",

abstract = "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.",

author = "Ewa Szymanska and Frydenvang, {Karla Andrea} and Pickering, {Darryl S} and Christian Krintel and Birgitte Nielsen and Ayesheh Kooshki and Zachariassen, {Linda Gr{\o}nborg} and Lars Olsen and Kastrup, {Jette Sandholm Jensen} and Johansen, {Tommy N{\o}rskov}",

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doi = "10.1021/acs.jmedchem.5b01666",

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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 - 2016/1/14

Y1 - 2016/1/14

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

SN - 0022-2623

VL - 59

SP - 448

EP - 461

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -

Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors

Abstract

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