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.

The critical roles played by GABAA receptors as inhibitory regulators of excitation in the central nervous system has been known for many years. Aberrant GABAA receptor function and trafficking deficits have also been associated with several diseases including anxiety, depression, epilepsy, and insomnia. As a consequence, important drug groups such the benzodiazepines, barbiturates, and many general anesthetics, have become established as modulators of GABAA receptor activity.Nevertheless, there is much we do not understand about the roles and mechanisms of GABAA receptors at neural network and systems levels. It is therefore crucial to develop novel technologies and especially chemical entities that can interrogate GABAA receptor function in the nervous system.Here, we describe the chemistry and characterization of a novel set of 4-PIOL and 4-PHP analogues synthesized with the aim of developing a toolkit of drugs that can photo-inactivate GABAA receptors.Most of these new analogues show higher affinities/potencies compared to the respective lead compounds. This is indicative of cavernous areas being present near their binding sites that can be potentially associated with novel receptor interactions. The 4-PHP azide-analogue, 2d, possesses particularly impressive nanomolar affinity/potency, and is an effective UV-inducible photo-inhibitor of GABAA receptors with considerable potential for photo-control of GABAA receptor function in situ.