A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure : Synthesis, resolution, pharmacology, and crystal structure. / Szymanska, Ewa; Frydenvang, Karla; Contreras-Sanz, Alberto; Pickering, Darryl S; Frola, Elena; Serafimoska, Zorica; Nielsen, Birgitte; Kastrup, Jette Sandholm; Johansen, Tommy Nørskov.

In: Journal of Medicinal Chemistry, Vol. 54, No. 20, 04.10.2011, p. 7289-7298.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Szymanska, E, Frydenvang, K, Contreras-Sanz, A, Pickering, DS, Frola, E, Serafimoska, Z, Nielsen, B, Kastrup, JS & Johansen, TN 2011, 'A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure', Journal of Medicinal Chemistry, vol. 54, no. 20, pp. 7289-7298. https://doi.org/10.1021/jm200862h

APA

Szymanska, E., Frydenvang, K., Contreras-Sanz, A., Pickering, D. S., Frola, E., Serafimoska, Z., ... Johansen, T. N. (2011). A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure. Journal of Medicinal Chemistry, 54(20), 7289-7298. https://doi.org/10.1021/jm200862h

Vancouver

Szymanska E, Frydenvang K, Contreras-Sanz A, Pickering DS, Frola E, Serafimoska Z et al. A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure. Journal of Medicinal Chemistry. 2011 Oct 4;54(20):7289-7298. https://doi.org/10.1021/jm200862h

Author

Szymanska, Ewa ; Frydenvang, Karla ; Contreras-Sanz, Alberto ; Pickering, Darryl S ; Frola, Elena ; Serafimoska, Zorica ; Nielsen, Birgitte ; Kastrup, Jette Sandholm ; Johansen, Tommy Nørskov. / A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure : Synthesis, resolution, pharmacology, and crystal structure. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 20. pp. 7289-7298.

Bibtex

@article{70a56675336c4235973dd0f218e05423,
title = "A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure",
abstract = "In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Ewa Szymanska and Karla Frydenvang and Alberto Contreras-Sanz and Pickering, {Darryl S} and Elena Frola and Zorica Serafimoska and Birgitte Nielsen and Kastrup, {Jette Sandholm} and Johansen, {Tommy N{\o}rskov}",
year = "2011",
month = "10",
day = "4",
doi = "10.1021/jm200862h",
language = "English",
volume = "54",
pages = "7289--7298",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",

}

RIS

TY - JOUR

T1 - A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure

T2 - Synthesis, resolution, pharmacology, and crystal structure

AU - Szymanska, Ewa

AU - Frydenvang, Karla

AU - Contreras-Sanz, Alberto

AU - Pickering, Darryl S

AU - Frola, Elena

AU - Serafimoska, Zorica

AU - Nielsen, Birgitte

AU - Kastrup, Jette Sandholm

AU - Johansen, Tommy Nørskov

PY - 2011/10/4

Y1 - 2011/10/4

N2 - In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.

AB - In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm200862h

DO - 10.1021/jm200862h

M3 - Journal article

VL - 54

SP - 7289

EP - 7298

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -

ID: 35084286