Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors

摘要

Abstract In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in?vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (?)-2-amino-3-(6-chloro-2′,5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R -isomer showing K i of 1.71?μM?at the GluA2 subtype, was found to competitively antagonize GluA2( Q ) i receptors in TEVC electrophysiological experiments ( K b ?= 2.13?μM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications. Graphical abstract Display Omitted Highlights ? New selective ligands for AMPA receptors were and synthesized based on the biphenylalanine scaffold. ? Selected enantiopure amino acids were evaluated for affinity at homomeric recombinant rat GluA2 and GluA3 receptors. ? Antagonist properties at homomeric GluA2 receptors for the most active compound were confirmed. ? Two alternative binding modes of synthesized compounds at GluA2 binding core were discussed.