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Article: Lonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
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TitleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
 
AuthorsGong, XD1
Wong, YL1
Leung, GPH1
Cheng, CY1
Silvestrini, B1
Wong, PYD1
 
Issue Date2000
 
PublisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
 
CitationBiology Of Reproduction, 2000, v. 63 n. 3, p. 833-838 [How to Cite?]
 
AbstractThe 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: Ionidamine 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 Ionidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC50 values of 170.6 and 631.5 μM, respectively; by comparison the IC50 value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 μM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and Ionidamine 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.
 
ISSN0006-3363
2013 Impact Factor: 3.451
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorGong, XD
 
dc.contributor.authorWong, YL
 
dc.contributor.authorLeung, GPH
 
dc.contributor.authorCheng, CY
 
dc.contributor.authorSilvestrini, B
 
dc.contributor.authorWong, PYD
 
dc.date.accessioned2012-10-30T06:12:51Z
 
dc.date.available2012-10-30T06:12:51Z
 
dc.date.issued2000
 
dc.description.abstractThe 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: Ionidamine 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 Ionidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC50 values of 170.6 and 631.5 μM, respectively; by comparison the IC50 value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 μM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and Ionidamine 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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationBiology Of Reproduction, 2000, v. 63 n. 3, p. 833-838 [How to Cite?]
 
dc.identifier.epage838
 
dc.identifier.issn0006-3363
2013 Impact Factor: 3.451
 
dc.identifier.issue3
 
dc.identifier.pmid10952928
 
dc.identifier.scopuseid_2-s2.0-0033842224
 
dc.identifier.spage833
 
dc.identifier.urihttp://hdl.handle.net/10722/171235
 
dc.identifier.volume63
 
dc.languageeng
 
dc.publisherSociety for the Study of Reproduction. The Journal's web site is located at http://www.biolreprod.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofBiology of Reproduction
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAnimals
 
dc.subject.meshBenzyl Compounds - Pharmacology
 
dc.subject.meshBicarbonates - Administration & Dosage
 
dc.subject.meshChloride Channels - Antagonists & Inhibitors - Physiology
 
dc.subject.meshChlorides - Administration & Dosage - Metabolism
 
dc.subject.meshCyclic Amp - Pharmacology
 
dc.subject.meshCystic Fibrosis Transmembrane Conductance Regulator - Antagonists & Inhibitors - Physiology
 
dc.subject.meshElectric Conductivity
 
dc.subject.meshEpididymis - Drug Effects - Physiology
 
dc.subject.meshEpithelial Cells - Drug Effects - Physiology
 
dc.subject.meshIndazoles - Pharmacology
 
dc.subject.meshMale
 
dc.subject.meshRats
 
dc.subject.meshRats, Sprague-Dawley
 
dc.titleLonidamine and analogue AF2785 block the cyclic adenosine 3',5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis
 
dc.typeArticle
 
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<contributor.author>Cheng, CY</contributor.author>
<contributor.author>Silvestrini, B</contributor.author>
<contributor.author>Wong, PYD</contributor.author>
<date.accessioned>2012-10-30T06:12:51Z</date.accessioned>
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<description.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: Ionidamine 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 Ionidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC50 values of 170.6 and 631.5 &#956;M, respectively; by comparison the IC50 value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 &#956;M. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and Ionidamine 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.</description.abstract>
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<subject.mesh>Animals</subject.mesh>
<subject.mesh>Benzyl Compounds - Pharmacology</subject.mesh>
<subject.mesh>Bicarbonates - Administration &amp; Dosage</subject.mesh>
<subject.mesh>Chloride Channels - Antagonists &amp; Inhibitors - Physiology</subject.mesh>
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<subject.mesh>Cyclic Amp - Pharmacology</subject.mesh>
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<subject.mesh>Electric Conductivity</subject.mesh>
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<subject.mesh>Epithelial Cells - Drug Effects - Physiology</subject.mesh>
<subject.mesh>Indazoles - Pharmacology</subject.mesh>
<subject.mesh>Male</subject.mesh>
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<title>Lonidamine and analogue AF2785 block the cyclic adenosine 3&apos;,5&apos;-monophosphate-activated chloride current and chloride secretion in the rat epididymis</title>
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Author Affiliations
  1. Chinese University of Hong Kong