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: V K Gribkoff, G Champigny, P Barbry, S I Dworetzky, N A Meanwell, M Lazdunski
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 269 Issue 15 Pg. 10983-6 (Apr 15 1994) ISSN: 0021-9258 [Print] United States
• PMID: 7512555 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Chloride Channels
• Chlorophenols
• Membrane Proteins
• Cystic Fibrosis Transmembrane Conductance Regulator
• Colforsin
• NS 004
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Chloride Channels (drug effects, physiology)
• Chlorophenols (pharmacology)
• Colforsin (pharmacology)
• Cystic Fibrosis Transmembrane Conductance Regulator
• Female
• Ion Channel Gating (drug effects, physiology)
• Kinetics
• Membrane Potentials (drug effects, physiology)
• Membrane Proteins (drug effects, physiology)
• Oocytes (drug effects, physiology)
• Plasmids
• Transfection
• Vero Cells
• Xenopus laevis