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

被引：4

作者：

Szymanska, Ewa ^{[1
]}

Nielsen, Birgitte ^{[2
]}

Johansen, Tommy N. ^{[2
]}

Moral, Ana Maria Cunado ^{[2
]}

Pickering, Darryl S. ^{[2
]}

Szczepanska, Katarzyna ^{[1
]}

Mickowska, Anna ^{[1
]}

Kiec-Kononowicz, Katarzyna ^{[1
]}

机构：

[1] Jagiellonian Univ, Med Coll, Dept Technol & Biotechnol Drugs, Medyczna 9, PL-30688 Krakow, Poland

[2] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, DK-2100 Copenhagen O, Denmark

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 138卷

关键词：

Ionotropic glutamate receptors; AMPA; GluA2; Phenylalanine; Competitive antagonist; Chiral resolution; Molecular modeling; CHIRAL STATIONARY-PHASE; GLUTAMATE RECEPTORS; ABSOLUTE STEREOCHEMISTRY; MOLECULAR PHARMACOLOGY; NEUROLOGICAL DISEASE; KAINATE RECEPTORS; CRYSTAL-STRUCTURE; ACID; RESOLUTION; DERIVATIVES;

D O I：

10.1016/j.ejmech.2017.07.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M at the GluA2 subtype, was found to competitively antagonize GluA2(Q)(i) receptors in TEVC electrophysiological experiments (K-b = 2.13 mu M). 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. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：874 / 883

页数：10

共 47 条

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