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

Ewa Szymanska; Karla Frydenvang; Alberto Contreras-Sanz; Darryl S Pickering; Elena Frola; Zorica Serafimoska; Birgitte Nielsen; Jette Sandholm Kastrup; Tommy Nørskov Johansen

doi:10.1021/jm200862h

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

Ewa Szymanska, Karla Frydenvang, Alberto Contreras-Sanz, Darryl S Pickering, Elena Frola, Zorica Serafimoska, Birgitte Nielsen, Jette Sandholm Kastrup, Tommy Nørskov Johansen

17 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	20
Pages (from-to)	7289-7298
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm200862h
Publication status	Published - 27 Oct 2011

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Former Faculty of Pharmaceutical Sciences

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10.1021/jm200862h

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Szymanska, E., Frydenvang, K., Contreras-Sanz, A., Pickering, D. S., Frola, E., Serafimoska, Z., Nielsen, B., Kastrup, J. S., & 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

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 et al.

In: Journal of Medicinal Chemistry, Vol. 54, No. 20, 27.10.2011, p. 7289-7298.

Research output: Contribution to journal › Journal article › Research › peer-review

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

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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.",

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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.

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

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