Aryl- and heteroaryl-substituted phenylalanines as AMPA receptor ligands

Abstract

A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3′-hydroxy-5-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4.6 μM for native AMPA receptors and over four-fold lower affinity for kainic acid receptors. Furthermore, 7e was evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. Recently reported X-ray structures 5CBR and 5CBS, representing two distinct antagonist binding modes, were used as templates for molecular docking of the synthesized series. Binding data supported with molecular modeling confirmed that aryl/heteroaryl-substituted phenylalanine analogues effectively bind to AMPA receptors with low micromolar affinity and high selectivity over native NMDA and kainate receptors. These properties make 7e a promising lead for the further development of new AMPA receptor ligands.

This article is protected by copyright. All rights reserved.

A series of racemic unnatural amino acids was rationally designed, synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most potent compound, (RS)-2-amino-3-(3′-hydroxy-5-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-3-yl)propanoic acid 7e with K_i of 4.6 μM at native AMPA receptors was further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The recently reported X-ray structures 5CBR and 5CBS representing two distinct AMPA antagonist binding modes were used as templates for molecular docking of the synthesized series.

http://ift.tt/2tO8LAs