title: Characterization of Lonidamine and AF2785 blockade of the cyclic AMP-activated chloride current in rat epididymal cells.
abstract: It has been shown previously that the antifertility agents Lonidamine and its analogue AF2785, [1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid] are potent inhibitors of the cAMP-activated chloride channel (CFTR) in rat epididymal cells. In this study, we further characterized the blocking actions of these two compounds and compared them with the known chloride channel blocker diphenylamine-2-carboxylate (DPC). Results show that the order of potency in blocking the cAMP-activated current is AF2785 > Lonidamine > DPC. All three compounds shared similar blocking characteristics. Firstly, their blockade of the current exhibited voltage dependence; all three agents blocked the current more markedly at negative than at positive membrane potentials. Secondly, they blocked the channels from the outside of the cell. Thirdly, their blocking efficacies were maximal at low extracellular pH. Lastly, the time course of the block by AF2785 and DPC appeared to be more rapid than that of Lonidamine. It is hoped that further studies with other indazole compounds will add knowledge to the physiology and pharmacology of CFTR in the epididymis. Such information will be of great importance to our quest for novel male contraceptives.
authors.affiliation: Department of Physiology, Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: X D
authors.initials: XD
authors.lastname: Gong
authors.forename: P Y
authors.initials: PY
authors.lastname: Wong
mesh_terms: D000818:Animals; D000988:Antispermatogenic Agents / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000378:metabolism; D004822:Epididymis / Q000166:cytology / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C415442:1-(2,4-dichlorobenzyl)indazole-3-acrylic acid; D000988:Antispermatogenic Agents; D001593:Benzyl Compounds; D002712:Chlorides; D007191:Indazoles; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C001209:fenamic acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C016371:lonidamine