Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ1 γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone |
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Authors: | Dr. Jacob Krall Benjamin M. Brygger Sara B. Sigurðardóttir Dr. Clarissa K. L. Ng Dr. Christoffer Bundgaard Dr. Jan Kehler Birgitte Nielsen Prof. Toke Bek Prof. Anders A. Jensen Prof. Bente Frølund |
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Affiliation: | 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;2. School of Molecular, Genetic and Population Health Sciences, The University of Edinburgh, Edinburgh, UK;3. Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark;4. Department of Ophthalmology, Faculty of Health, Aarhus University, Aarhus, Denmark |
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Abstract: | The ρ‐containing γ‐aminobutyric acid type A receptors (GABAARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAARs are of interest. In this study, we demonstrate that the partial GABAAR 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 GABAARs in a [3H]muscimol binding assay and at recombinant human α1β2γ2S and ρ1 GABAARs 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 ρ1 GABAAR that also displayed significant selectivity for this receptor over the α1β2γ2S GABAAR. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes. |
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Keywords: | GABAC receptors imidazole-4-acetic acid retinal vascular tone structure– activity relationships ρ GABAA receptors |
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