title: Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology.
abstract: Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, K B = 10 μM) and selectivity (greater than 100 times at ρ1 GABAC receptors as compared to α1β2γ2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors.forename: Navnath
authors.initials: N
authors.lastname: Gavande
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors.forename: Izumi
authors.initials: I
authors.lastname: Yamamoto
authors.affiliation: Schrodinger, Inc., 8910 University Center Lane, Suite 270, San Diego, California, United States.
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.affiliation: Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney, NSW, Australia.
authors.forename: Tu-Hoa
authors.initials: TH
authors.lastname: Ai
authors.affiliation: Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney, NSW, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Burden
authors.affiliation: Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney, NSW, Australia.
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
keywords: GABA receptors; cyclic phosphinic acids; ligand-gated ion channels; two-electrode voltage clamp; γ-Aminobutyric acid; ρ1 GABAC homology model