Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone

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 α1β2γ2Sand ρ1GABAARs 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 ρ1GABAAR that also displayed significant selectivity for this receptor over the α1β2γ2SGABAAR. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.