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1-[1-Hexyl-6-(methyloxy)-1H-indazol-3-yl]-2-methyl-1-propanone, a Potent and Highly Selective Small Molecule Blocker of the Large-Conductance Voltage-Gated and Calcium-Dependent K+ Channel

Zeng, Haoyu ; Gordon, Earl ; Lin, Zuojun ; Lozinskaya, Irina M ; Willette, Robert N ; Xu, Xiaoping

The Journal of pharmacology and experimental therapeutics, 2008-10, Vol.327 (1), p.168-177 [Peer Reviewed Journal]

United States: American Society for Pharmacology and Experimental Therapeutics

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Title:
1-[1-Hexyl-6-(methyloxy)-1H-indazol-3-yl]-2-methyl-1-propanone, a Potent and Highly Selective Small Molecule Blocker of the Large-Conductance Voltage-Gated and Calcium-Dependent K+ Channel
Author: Zeng, Haoyu ; Gordon, Earl ; Lin, Zuojun ; Lozinskaya, Irina M ; Willette, Robert N ; Xu, Xiaoping
Subjects: Action Potentials - drug effects ; Animals ; Calcium Channels - drug effects ; CHO Cells ; Cricetinae ; Cricetulus ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels - drug effects ; Guinea Pigs ; Humans ; Indazoles - pharmacology ; Indoles - pharmacology ; KCNQ1 Potassium Channel - drug effects ; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors ; Large-Conductance Calcium-Activated Potassium Channels - chemistry ; Large-Conductance Calcium-Activated Potassium Channels - physiology ; Peptides - pharmacology ; Potassium Channel Blockers - pharmacology ; Rabbits ; Sodium Channels - drug effects
Is Part Of: The Journal of pharmacology and experimental therapeutics, 2008-10, Vol.327 (1), p.168-177
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: The large-conductance voltage-gated and calcium-dependent K + (BK) channels are widely distributed and play important physiological roles. Commonly used BK channel inhibitors are peptide toxins that are isolated from scorpion venoms. A high-affinity, nonpeptide, synthesized BK channel blocker with selectivity against other ion channels has not been reported. We prepared several compounds from a published patent application ( Doherty et al., 2004 ) and identified 1-[1-hexyl-6-(methyloxy)-1 H -indazol-3-yl]-2-methyl-1-propanone (HMIMP) as a potent and selective BK channel blocker. The patch-clamp technique was used for characterizing the activity of HMIMP on recombinant human BK channels (Î± subunit, Î±+Î²1 and Î±+Î²4 subunits). HMIMP blocked all of these channels with an IC 50 of â¼2 nM. The inhibitory effect of HMIMP was not voltage-dependent, nor did it require opening of BK channels. HMIMP also potently blocked BK channels in freshly isolated detrusor smooth muscle cells and vagal neurons. HMIMP (10 nM) reduced the open probability significantly without affecting single BK-channel current in inside-out patches. HMIMP did not change the time constant of open states but increased the time constants of the closed states. More importantly, HMIMP was highly selective for the BK channel. HMIMP had no effect on human Na V 1.5 (1 Î¼M), Ca V 3.2, L-type Ca 2+ , human ether-a-go-go-related gene potassium channel, KCNQ1+minK, transient outward K + or voltage-dependent K + channels (100 nM). HMIMP did not change the action potentials of ventricular myocytes, confirming its lack of effect on cardiac ion channels. In summary, HMIMP is a highly potent and selective BK channel blocker, which can serve as an important tool in the pharmacological study of the BK channel.
Publisher: United States: American Society for Pharmacology and Experimental Therapeutics
Language: English

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1-[1-Hexyl-6-(methyloxy)-1H-indazol-3-yl]-2-methyl-1-propanone, a Potent and Highly Selective Small Molecule Blocker of the Large-Conductance Voltage-Gated and Calcium-Dependent K+ Channel

Zeng, Haoyu ; Gordon, Earl ; Lin, Zuojun ; Lozinskaya, Irina M ; Willette, Robert N ; Xu, Xiaoping

United States: American Society for Pharmacology and Experimental Therapeutics

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