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

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    19 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 languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume54
    Issue number20
    Pages (from-to)7289-7298
    ISSN0022-2623
    DOIs
    Publication statusPublished - 4 Oct 2011

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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