Abstract
Lonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
Gong,Xiandi; Wong,Y.L.; Leung,George P.H.; Cheng,Chuen-yan; Silvestrini,Bruno; Wong,Patrick Y.D.
Biology of Reproduction 63(3): 833-838
Publication date: 2000
The cystic fibrosis transmembrane conductance regulator (CFTR)or the small conductance cAMP-activated chloride channel encodedby the CFTR gene has been shown to play an important role inthe formation of the epididymal fluid microenvironment. Mutationof the gene has led to widespread effects on male reproduction.Like other ion channels, CFTR is amenable to pharmacologicalintervention. Blocking CFTR in the epididymis could in principlelead to disruption of the epididymal fluid environment. We reportfor the first time two indazole compounds: lonidamine and 1-(2,4-dichlorobenzyl)-indazole-3-acrylicacid (AF2785) are potent blockers of CFTR in the epididymis.When added to the external solution under whole-cell patch clampconditions, AF2785 and lonidamine inhibited the cAMP-activatedchloride current in rat epididymal cells with apparent ICvalues of 170.6 and 631.5 µM, respectively; by comparisonthe IC value for diphenylamine-2-carboxylate, a well-knownchloride channel blocker was 1294 µM. In cultured ratepididymal epithelia mounted in a Ussing chamber, AF2785 andlonidamine inhibited the cAMP-stimulated short-circuit current(a measure of chloride secretion) when added to the apical bathingsolution with potency greater than any known chloride channelstudied. It is proposed that in view of the important role CFTRplays in male reproduction, further study with these and othernew indazole compounds for their CFTR blocking actions can providea new avenue of research into the development of novel malecontraceptives.
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