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.
abstract: 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)-1H-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 (alpha subunit, alpha+beta1 and alpha+beta4 subunits). HMIMP blocked all of these channels with an IC(50) of approximately 2 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 microM), 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.
authors.affiliation: Metabolic Pathway Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Zeng
authors.forename: Earl
authors.initials: E
authors.lastname: Gordon
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Lin
authors.forename: Irina M
authors.initials: IM
authors.lastname: Lozinskaya
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D015220:Calcium Channels / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D051657:KCNQ1 Potassium Channel / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects
chemical_list: C532126:1-(1-hexyl-6-(methyloxy)-1H-indazol-3-yl)-2-methyl-1-propanone; D015220:Calcium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007191:Indazoles; D007211:Indoles; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D015222:Sodium Channels; C048220:paxilline; C064719:iberiotoxin