title: The substituted benzimidazolone NS004 is an opener of the cystic fibrosis chloride channel.
abstract: Cystic fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs. Epithelial cells of cystic fibrosis patients have a decreased capacity to secrete chloride in response to cAMP-mobilizing agents because of the mutation of a single gene. The gene product, the cystic fibrosis transmembrane conductance regulator or CFTR, is a chloride channel. The most frequent mutation is a deletion of phenylalanine in position 508 (delta F508-CFTR) that reduces both the expression of the CFTR protein at the cell surface, and the activity of the Cl- channel. This work presents the properties of NS004, a substituted benzimidazolone, which is the first activator of normal and mutant CFTR-associated chloride channels to be described. NS004 activated CFTR and delta F508-CFTR Cl- channels expressed in Xenopus oocytes, and increased 125I efflux (via the Cl- channel) from Vero cells expressing CFTR and delta F508-CFTR. Application of NS004 to the external side of outside-out patches excised from these CFTR- and delta F508-CFTR-expressing cells induced a marked and reversible increase in channel activity.
authors.affiliation: Department of Central Nervous System Biophysics and Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492.
authors.forename: V K
authors.initials: VK
authors.lastname: Gribkoff
authors.forename: G
authors.initials: G
authors.lastname: Champigny
authors.forename: P
authors.initials: P
authors.lastname: Barbry
authors.forename: S I
authors.initials: SI
authors.lastname: Dworetzky
authors.forename: N A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: M
authors.initials: M
authors.lastname: Lazdunski
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D002733:Chlorophenols / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D010957:Plasmids; D014162:Transfection; D014709:Vero Cells; D014982:Xenopus laevis
chemical_list: D001562:Benzimidazoles; D018118:Chloride Channels; D002733:Chlorophenols; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; C083230:NS 004; D015056:1-Methyl-3-isobutylxanthine