title: Experimental Evaluation of Proposed Small-Molecule Inhibitors of Water Channel Aquaporin-1.
abstract: The aquaporin-1 (AQP1) water channel is a potentially important drug target, as AQP1 inhibition is predicted to have therapeutic action in edema, tumor growth, glaucoma, and other conditions. Here, we measured the AQP1 inhibition efficacy of 12 putative small-molecule AQP1 inhibitors reported in six recent studies, and one AQP1 activator. Osmotic water permeability was measured by stopped-flow light scattering in human and rat erythrocytes that natively express AQP1, in hemoglobin-free membrane vesicles from rat and human erythrocytes, and in plasma membrane vesicles isolated from AQP1-transfected Chinese hamster ovary cell cultures. As a positive control, 0.3 mM HgCl2 inhibited AQP1 water permeability by >95%. We found that none of the tested compounds at 50 µM significantly inhibited or increased AQP1 water permeability in these assays. Identification of AQP1 inhibitors remains an important priority.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteva-Font
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.).
authors.forename: Byung-Ju
authors.initials: BJ
authors.lastname: Jin
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.).
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.).
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.).
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, California (C.E.-F., B.-J.J., S.L., P.-W.P., A.S.V.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.) Alan.Verkman@ucsf.edu.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D009995:Osmosis / Q000187:drug effects; D017208:Rats, Wistar; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000378:metabolism
chemical_list: D005452:Fluoresceins; D006454:Hemoglobins; D054852:Small Molecule Libraries; D014867:Water; D051398:Aquaporin 1; C007740:fluorexon