Discovery of alpha-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of rho(1) gamma-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone

作者：Krall Jacob; Brygger Benjamin M; Siguroardottir Sara B; Ng Clarissa K L; Bundgaard Christoffer; Kehler Jan; Nielsen Birgitte; Bek Toke; Jensen Anders A; Frolund Bente^*

来源：ChemMedChem, 2016, 11(20): 2299-2310.

DOI：10.1002/cmdc.201600356

• GABA(C) receptors
• imidazole-4-acetic acid
• retinal vascular tone
• structure-activity relationships
• rho GABA(A) receptors

The 1-containing gamma-aminobutyric acid typeA receptors (GA-BA(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 alpha-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 [H-3]muscimol binding assay and at recombinant human alpha(1)beta(2)beta(2S) and rho(1) GABA(A)Rs using the FLIPR (TM) membrane potential assay. The (+)-alpha-methyl- and alpha-cyclopropyl-substituted IAA analogues ((+)-6a and 6c, respectively) were identified as fairly potent antagonists of the rho(1) GABA(A)R that also displayed significant selectivity for this receptor over the alpha(1)beta(2)gamma(2S) GABA(A)R. Both 6a and 6c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.

• 出版日期2016-10-19