Design, Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors

摘要

The ρ1 GABAC receptor is a ligand-gated chloride ion channel that shows promise as a therapeutic target for myopia, sleep disorders, memory and learning facilitation, and anxiety- related disorders. As such, there is a need for molecular probes to understand the role GABAC receptors play in physiological and pathological processes. To date, no labeled (either radioactive or ?uorescent) GABAC selective ligand has been developed that can act as a marker for GABAC receptor visualization and localization studies. Herein, we report a series of ?uorescent ligands containing different-sized linkers and ?uorophores based around (S)-4-ACPBPA [(4-aminocyclopenten-1-yl)-butylphosphinic acid], a selective GABAC antagonist. One of these conjugates, (S)-4-ACPBPA-C5-BODIPY (13), displayed moderate potency (IC50 = 58.61 μM) and selectivity (>100 times) for ρ1 over α1β2γ2L GABAA receptors. These conjugates are novel lead agents for the development of more potent and selective ?uorescent probes for studying the localization and function of GABAC receptors in living cells.