title: Lonidamine and analogue AF2785 block the cyclic adenosine 3', 5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) or the small conductance cAMP-activated chloride channel encoded by the CFTR gene has been shown to play an important role in the formation of the epididymal fluid microenvironment. Mutation of the gene has led to widespread effects on male reproduction. Like other ion channels, CFTR is amenable to pharmacological intervention. Blocking CFTR in the epididymis could in principle lead to disruption of the epididymal fluid environment. We report for the first time two indazole compounds: lonidamine and 1-(2, 4-dichlorobenzyl)-indazole-3-acrylic acid (AF2785) are potent blockers of CFTR in the epididymis. When added to the external solution under whole-cell patch clamp conditions, AF2785 and lonidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC(50) values of 170.6 and 631.5 microM, respectively; by comparison the IC(50) value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 microM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and lonidamine inhibited the cAMP-stimulated short-circuit current (a measure of chloride secretion) when added to the apical bathing solution with potency greater than any known chloride channel studied. It is proposed that in view of the important role CFTR plays in male reproduction, further study with these and other new indazole compounds for their CFTR blocking actions can provide a new avenue of research into the development of novel male contraceptives.
authors.affiliation: Department of Physiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: X D
authors.initials: XD
authors.lastname: Gong
authors.forename: Y L
authors.initials: YL
authors.lastname: Wong
authors.forename: G P
authors.initials: GP
authors.lastname: Leung
authors.forename: C Y
authors.initials: CY
authors.lastname: Cheng
authors.forename: B
authors.initials: B
authors.lastname: Silvestrini
authors.forename: P Y
authors.initials: PY
authors.lastname: Wong
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D001639:Bicarbonates / Q000008:administration & dosage; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D002712:Chlorides / Q000008:administration & dosage / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000502:physiology; D004553:Electric Conductivity; D004822:Epididymis / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C415442:1-(2,4-dichlorobenzyl)indazole-3-acrylic acid; D001593:Benzyl Compounds; D001639:Bicarbonates; D018118:Chloride Channels; D002712:Chlorides; D007191:Indazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; C016371:lonidamine