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

• Published in: ChemMedChem Vol. 11; no. 20; pp. 2299 - 2310
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Germany 19.10.2016
• Subjects: Animals; Arterioles - drug effects; Arterioles - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Eye - drug effects; Humans; Imidazoles - administration & dosage; Imidazoles - chemistry; Imidazoles - pharmacology; Mice; Molecular Structure; Receptors, GABA-A - metabolism; Retinal Vessels - drug effects; Retinal Vessels - metabolism; Structure-Activity Relationship; Swine; imidazole-4-acetic acid; GABAC receptors; retinal vascular tone; structure-activity relationships; ρ GABAA receptors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600356

The ρ-containing γ-aminobutyric acid type A receptors (GABA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABA Rs are of interest. In this study, we demonstrate that the partial GABA 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 Rs in a [ H]muscimol binding assay and at recombinant human α β γ and ρ  GABA 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  GABA R that also displayed significant selectivity for this receptor over the α β γ GABA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.