165115-24-2Relevant academic research and scientific papers
A new phenylalanine derivative acts as an antagonist at the AMPA Receptor GluA2 and introduces partial domain closure: Synthesis, resolution, pharmacology, and crystal structure
Szymańska, Ewa,Frydenvang, Karla,Contreras-Sanz, Alberto,Pickering, Darryl S.,Frola, Elena,Serafimoska, Zorica,Nielsen, Birgitte,Kastrup, Jette S.,Johansen, Tommy N.
, p. 7289 - 7298 (2011/12/04)
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 GluA1o 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.
