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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Alberto
authors.initials: A
authors.lastname: Contreras-Sanz
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Elena
authors.initials: E
authors.lastname: Frola
authors.forename: Zorica
authors.initials: Z
authors.lastname: Serafimoska
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D005260:Female; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: C568956:2-amino-3-(2-(2-carboxyethyl)-5-chloro-4-nitrophenyl)propionic acid; D018091:Receptors, AMPA; D010649:Phenylalanine