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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• 作者：Ewa Szyma艅ska ; Karla Frydenvang ; Alberto Contreras-Sanz ; Darryl S. Pickering ; Elena Frola ; Zorica Serafimoska ; Birgitte Nielsen ; Jette S. Kastrup ; Tommy N. Johansen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7289-7298
• 全文大小：1019K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

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掳. 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.