Chloride channels as drug targets.
Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABA(A) (gamma-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery.
Verkman
Alan S
AS
Departments of Medicine and Physiology, University of California, San Francisco, California 94143-0521, USA. Alan.Verkman@ucsf.edu
Galietta
Luis J V
LJ
D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism / Q000502:physiology; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*
C505032:CFTR protein, human; C492109:CLCA1 protein, human; D018118:Chloride Channels; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator