Pharmacology of High-Conductance, Ca2+-Activated Potassium Channels

García, María L.; Kaczorowski, Gregory J.

doi:10.1007/978-1-4615-1303-2_13

Cited by 6 publications

(6 citation statements)

References 64 publications

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“…A number of BK Ca channel openers have been described and shown to enhance BK Ca channel activity in electrophysiological (reviewed by Garcia and Kaczorowski, 2001), in vitro (Sheldon et al, 1997;Butera et al, 2001;Malysz et al, 2004) and in vivo experiments (Fox et al, 1997;Sivarao, et al, 2005). It is believed that compounds which enhance BK Ca channel activity are potential therapies in various pathophysiological conditions such as hypertension, cardiac ischemia, stroke and smooth muscle hyperactivity (Gribkoff et al, 2001;Shieh et al, 2000;Coghlan et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of intestinal motility by the putative BKCa channel opener LDD175

et al. 2009

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LDD175 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) is a benzofuroindole compound characterized previously as a potent opener of the large conductance calcium activated (BK(Ca)) channels. Activators of the BK(Ca) channels are potential therapies for smooth muscle hyperactivity disorders. The present study investigates the influence of LDD175 on the mechanical activity of the ileum smooth muscle. LDD175 inhibited spontaneous contractions of the ileum in a concentration-dependent manner (pEC(50)=5.9 +/- 0.1) (E (max)=96 +/- 1.0% at 100 muM, n=3). It also remarkably inhibited contractions due to acetylcholine (ACh) (pEC(50)=5.3 +/- 0.1)(E (max)=97.7 +/- 2.3%, n=6) and electrical field stimulation (EFS) (pEC(50)=5.5 +/- 0.1) (E (max)=83.3 +/- 6.0%, n=6). In strips precontracted by 20 mM KCl, LDD175 significantly reduced the contractions yielding a pEC(50) of 6.1 +/- 0.1 and E (max) of 96.6 +/- 0.9%, (n=6). In 60 mM KCl, a concentration-dependent inhibition was observed with respective pEC(50) and E (max) values of 4.1 +/- 0.1 and 50.8 +/- 5.0% (n=3). BK(Ca) channel blockers iberiotoxin (IbTX) and tetraethylammonium chloride (TEA, 1 mM) attenuated the relaxative effect of LDD175 but not barium chloride (BaCl(2)), and glibenclamide (K(IR) and K(ATP) channel blockers, respectively). These data demonstrate the antispasmodic activity of LDD175 attributable to the potentiation of the BK(Ca) channels.

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Section: Discussionmentioning

confidence: 99%

Inhibition of intestinal motility by the putative BKCa channel opener LDD175

et al. 2009

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“…Since peptidyl modulators of ion channels are abundant in venoms, they are rich sources for reagents useful in proof of concept studies. In addition, small molecule natural product channel modulators, including indole diterpene blockers of high conductance, calciumactivated potassium channels (KCNMA1), have been used as probes in target validation studies ( Garcia and Kaczorowski, 2001 ).…”

Section: Identifi Cation and Validation Of Ion Channel Targetsmentioning

confidence: 99%

Ion Channels as Drug Targets: The Next GPCRs

Kaczorowski

McManus

Priest

et al. 2008

The Journal of General Physiology

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173

126

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Correspondence to Owen McManus: o w e n _ m c m a n u s @ m e r c k . c o m Ion channels are well recognized as important therapeutic targets for treating a number of different pathophysiologies. Historically, however, development of drugs targeting this protein class has been diffi cult. Several challenges associated with molecular-based drug discovery include validation of new channel targets and identifi cation of acceptable medicinal chemistry leads. Proof of concept approaches, focusing on combined molecular biological/pharmacological studies, have been successful. New, functional, high throughput screening (HTS) strategies developed to identify tractable lead structures, which typically are not abundant in small molecule libraries, have also yielded promising results. Automated cell-based HTS assays can be confi gured for many different types of ion channels using fl uorescence methods to monitor either changes in membrane potential or intracellular calcium with high density format plate readers. New automated patch clamp technologies provide secondary screens to confi rm the activity of hits at the channel level, to determine selectivity across ion channel superfamilies, and to provide insight into mechanism of action. The same primary and secondary assays effectively support medicinal chemistry lead development. Together, these methodologies, along with classical drug development practices, provide an opportunity to discover and optimize the activity of ion channel drug development candidates. A case study with voltage-gated sodium channels is presented to illustrate these principles.

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“…Iberiotoxin (IbTX), a 37amino acid peptide isolated from the venom of the scorpion Buthus tamulus and having a block mechanism analogous to that of ChTX [54], is the first example of a high affinity inhibitor of BK channels [55] and is probably the most used BK-blocker for experimental purposes (half maximal concentration: 10 nM [56]). Nevertheless, as of today, given the pharmaceutical disadvantages as a result of their peptide nature (not orally active, poor blood-brain permeability, disadvantages about synthesis and so on), these and other related peptide toxins, such as limbatustoxin (LbTx) [57], do not represent potential therapeutic agents, but they are considered as powerful tools to delineate Review the channel pore structure and the mechanism of ion permeation as well as to study the physiological role of the BK-channel subtype. However, the list of scorpion toxins with BK-blocker properties is destined to grow quickly {as also demonstrated from the recent publication of a new specific BK-blocker, a 37-amino acid toxin, named slotoxin (SloTx) and isolated from Centruroides noxius [58], that could even distinguish between a and a + b complexes} and to be enriched by peptide toxins isolated from other animal venoms, such as from snake's venom [59], all speeded up by established experimental methodologies developed for scorpion toxins.…”

Section: Natural Bk-blockersmentioning

confidence: 99%

Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

Nardi

Calderone²,

Chericoni³

et al. 2003

Planta med

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IntroductionAmong the different factors exerting an influence on the activity of the different classes of potassium (K + ) channels, a rise in the intracellular concentration of free calcium ions causes the activation of a family of channels, known as calcium-activated channels. Calcium-activated K + channels are further classified into three principal subtypes on the basis of their biophysical single channel conductance: probably, the most studied subtype is represented by the large-conductance calcium-activated K + channels, also known as BK, BK Ca or Maxi-K channels. Besides their calcium-dependent activation, BK channels possess also a voltage-operated mechanism, and this peculiarity accounts for the highly effective role of feed-back regulation against the rise of intracellular Ca 2+ and membrane depolarisation, promoting a massive outward flow of K + ions and leading to a membrane hyperpolarisation, i. e., to a stabilisation of the cell [1].As far as molecular structure is concerned, the BK channel is a tetrameric protein complex formed by four a subunits, shaping the channel pore. AbstractLarge-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cell, including neurons and myocytes, where they play an essential role in the regulation of cell excitability and function. These properties open a possible role for BK-activators (also called BK-openers) and/or BK-blockers as effective therapeutic agents for different neurological, urological, respiratory and cardiovascular diseases. The synthetic benzimidazolone derivatives NS004 and NS1619 are the pioneer BK-activators and have represented the reference models which led to the design of several novel and heterogeneous synthetic BK-openers, while very few synthetic BK-blockers have been reported. Even today, the research towards identifying new BK-modulating agents is proceeding with great impetus and is giving an ever-increasing number of new molecules. Among these, also a handsome number of natural BK-modulator compounds, belonging to different structural classes, has appeared in the literature. The goal of this paper is to provide a possible simple classification of the broad structural heterogeneity of the natural BK-activating agents (terpenes, phenols, flavonoids) and blockers (alkaloids and peptides), and a concise overview of their chemical and pharmacological properties as well as potential therapeutic applications.

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Pharmacology of High-Conductance, Ca2+-Activated Potassium Channels

Cited by 6 publications

References 64 publications

Inhibition of intestinal motility by the putative BKCa channel opener LDD175

Inhibition of intestinal motility by the putative BKCa channel opener LDD175

Ion Channels as Drug Targets: The Next GPCRs

Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

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