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. (13th September 2016) - Krall, Jacob
Abstract: The ρ‐containing γ‐aminobutyric acid type A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA 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 froml ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [ 3 H]muscimol binding assay and at recombinant human α1 β2 γ2S and ρ1 GABAA Rs using the FLIPR™ membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐6 a and6 c, respectively) were identified as fairly potent antagonists of the ρ1 GABAA R that also displayed significant selectivity for this receptor over the α1 β2 γ2S GABAA R. Both6 a and6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes. Abstract : Insight in sight : New potent and selective ρ GABAA receptor (GABAA R) antagonists were obtained by the introduction of small substituents at the α‐position of the acetic acid side chain of imidazole‐4‐acetic acid, a dual active ρ1 /α1 β2 γ2S GABAA R agonist. The ρ1 GABAA R antagonist effects of the (+)‐α‐methyl‐substituted analogue (+)‐6 a and α‐cyclopropyl analogue6 c were shown to be translated to a blocking effect of GABA‐induced relaxation on retinal porcine arterioles.