Abstract:
:Dantrolene was recently identified as a novel inhibitor of the plasmodial surface anion channel (PSAC), an unusual ion channel on Plasmodium falciparum-infected human red blood cells. Because dantrolene is used clinically, has a high therapeutic index, and has desirable chemical synthetic properties, it may be a lead compound for antimalarial development. However, dantrolene derivatives would need to preferentially interact with PSAC over the sarcoplasmic reticulum (SR) Ca2+ release channel to avoid unwanted side effects from antimalarial therapy. Furthermore, dantrolene's modest affinity for PSAC (K(m) of 1.2 microM) requires improvement. In this study, we tested 164 derivatives of dantrolene to examine whether these hurdles can be surmounted. A simple screen for PSAC block defined the minimal scaffold needed and identified compounds with > or =5-fold higher affinity. Single-channel patch-clamp recordings on infected human red blood cells with two derivatives also revealed increased blocking affinity that resulted from slower unbinding from a site on the extracellular face of PSAC. We tested these derivatives in a frog skeletal muscle contractility assay and found that, in contrast to dantrolene, they had little or no effect on SR Ca2+ release. Finally, these blockers kill in vitro parasite cultures at lower concentrations than dantrolene, consistent with an essential role for PSAC. Because, as a class, these derivatives fulfil the requirements for drug leads and can be studied with simple screening technology, more extensive medicinal chemistry is warranted to explore antimalarial development.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kang M,Lisk G,Hollingworth S,Baylor SM,Desai SAdoi
10.1124/mol.104.010553keywords:
subject
Has Abstractpub_date
2005-07-01 00:00:00pages
34-40issue
1eissn
0026-895Xissn
1521-0111pii
mol.104.010553journal_volume
68pub_type
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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pub_type: 杂志文章
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更新日期:2004-02-01 00:00:00
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更新日期:2003-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:2009-03-01 00:00:00
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更新日期:2001-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-06-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:2008-02-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1990-03-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1992-07-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1984-01-01 00:00:00
abstract::Amphetamine congeners [e.g., 3,4-methylenedioxymetamphetamine (MDMA), or "ecstasy"] are substrates for monoamine transporters (i.e., the transporters for serotonin, norepinephrine, and dopamine); however, their in vivo-action relies on their ability to promote monoamine efflux. The mechanistic basis for this counter t...
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更新日期:1985-01-01 00:00:00
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