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Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ 1 γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone
Author(s) -
Krall Jacob,
Brygger Benjamin M.,
Sigurðardóttir Sara B.,
Ng Clarissa K. L.,
Bundgaard Christoffer,
Kehler Jan,
Nielsen Birgitte,
Bek Toke,
Jensen Anders A.,
Frølund Bente
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600356
Subject(s) - muscimol , gabaa receptor , chemistry , acetic acid , agonist , receptor , aminobutyric acid , retinal , in vivo , stereochemistry , biochemistry , pharmacology , biology , microbiology and biotechnology
The ρ‐containing γ‐aminobutyric acid type A receptors (GABA A Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABA A Rs are of interest. In this study, we demonstrate that the partial GABA A R agonist imidazole‐4‐acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α‐ and N ‐alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABA A Rs in a [ 3 H]muscimol binding assay and at recombinant human α 1 β 2 γ 2S and ρ 1 GABA A Rs using the FLIPR™ membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐ 6 a and 6 c , respectively) were identified as fairly potent antagonists of the ρ 1 GABA A R that also displayed significant selectivity for this receptor over the α 1 β 2 γ 2S GABA A R. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes.