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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 LU ; Nielsen, Anne-Birgitte; Kooshki, Ayesheh; Zachariassen, Linda Grønborg; Olsen, Lars; Kastrup, Jette Sandholm Jensen and Johansen, Tommy Nørskov (2016) In Journal of Medicinal Chemistry 59(1). p.448-461
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... (More)
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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Medicinal Chemistry
volume
59
issue
1
pages
448 - 461
publisher
American Chemical Society (ACS)
external identifiers
  • scopus:84955159926
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.5b01666
language
English
LU publication?
no
id
0b2ab2cb-1f7d-4c05-8293-01e21d5f9d11
date added to LUP
2017-06-10 06:45:16
date last changed
2017-09-13 03:00:03
@article{0b2ab2cb-1f7d-4c05-8293-01e21d5f9d11,
  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       = {Szymanska, Ewa and Frydenvang, Karla Andrea and Pickering, Darryl S and Krintel, Christian and Nielsen, Anne-Birgitte and Kooshki, Ayesheh and Zachariassen, Linda Grønborg and Olsen, Lars and Kastrup, Jette Sandholm Jensen and Johansen, Tommy Nørskov},
  issn         = {1520-4804},
  language     = {eng},
  number       = {1},
  pages        = {448--461},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.5b01666},
  volume       = {59},
  year         = {2016},
}