title: Design, Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors.
abstract: 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 fluorescent) 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 fluorescent ligands containing different-sized linkers and fluorophores 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 fluorescent probes for studying the localization and function of GABAC receptors in living cells.
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Navnath
authors.initials: N
authors.lastname: Gavande
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Kim
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Munikumar R
authors.initials: MR
authors.lastname: Doddareddy
authors.affiliation: Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Sydney, NSW 2006, Australia.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
keywords: CNS-related disorders; GABAC antagonists; Human ρ1 GABAC receptors; fluorescent and biotinylated probes; homology modeling and docking