Shaker‐type Kv1 channel blockers increase the peristaltic activity of guinea‐pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system

Abstract

1 A constant intraluminal pressure system was used to evaluate the e ects of Kv1 channel blockers on the peristaltic activity of guinea-pig ileum. 2 The nortriterpene correolide, a non-selective inhibitor of all Kv1 sub-types, causes progressive and sustained reduction of the pressure threshold for eliciting peristaltic contractions. 3 Margatoxin (MgTX), alpha-dendrotoxin (a-DTX) and dendrotoxin-K (DTX-K), highly selective peptidyl inhibitors of certain Kv1 sub-types, cause immediate reduction of the pressure threshold. This e ect subsides with time, irrespective of the peptides' concentration in the bath. In preparations pretreated with saturating concentrations of MgTX, correolide further stimulates the peristaltic activity. 4 Iberiotoxin (IbTX), a selective inhibitor of the high-conductance Ca 2+ -activated K + (BK) channels, and charybdotoxin (ChTX), which inhibits Kv1.2 and Kv1.3 as well as BK channels, fail to stimulate the peristaltic activity. 5 Blockade of muscarinic receptors by atropine reduces, and occasionally suppresses the peristaltic activity of guinea-pig ileum. In atropine-treated preparations, correolide and MgTX retain their abilities to reduce the pressure threshold and are able to restore the peristaltic re¯ex in the preparations where this re¯ex was suppressed by atropine. 6 The stimulatory e ect of correolide and MgTX in atropine-treated preparations is abolished by subsequent addition of selective antagonists of both NK1 and NK2 receptors. 7 In conclusion, blockade of Kv1, particularly Kv1.1 channels, increases the peristaltic activity of guinea-pig ileum by enhancing the release of neurotransmitters at the enteric nervous system. In contrast, stimulation of the myogenic motility by blockade of BK channels does not a ect the threshold for the peristaltic re¯ex.

A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library

“…Toxins were added after 60 min of equilibration (34). For assays of peristalsis, intraluminal perfusion from the oral end was continuous with pressure recording at the aboral end using the threshold for contraction to quantify effects (12). Toxins were added after peristaltic activity was stable for Ͼ15 min.…”

“…Regrettably, these natural and synthetic ligands have proven inadequate. For example, kaliotoxin-1 (KTX) (9) inhibits Kv1.3 to suppress T cell activity (10) but also blocks Kv1.1 and Kv1.2 (11) with sufficient potency to produce undesirable side effects such as diarrhea (12). Efforts to improve selectivity continue (2,3,13,14).…”

Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels

“…When MgTx was isolated and its high affinity interaction with Kv1.3 was precisely characterized it was only tested on a limited number of channels excluding Kv1.1, Kv1.2 and Kv1.4 channels, those with high sequence homology to Kv1.3 (Garcia-Calvo et al, 1993). Later the authors who described MgTx and other workgroups refer to the peptide as potent blocker of Kv1.1, Kv1.2 and Kv1.3 channels (Anangi et al, 2012;Koch et al, 1997;SuarezKurtz et al, 1999;Vianna-Jorge et al, 2003) whereas the references do not describe or contain any information about the interaction of MgTx and the Kv1.1 or Kv1.2 channels. Without the precise characterization of the selectivity profile of MgTx, results from radioactively labeled MgTx binding assays, observed potassium current block or other biological effects of the peptide may not be considered as a direct proof of Kv1.3 expression.…”

Spiro azepane-oxazolidinones as Kv1.3 potassium channel blockers: WO2010066840

“…In addition to avoiding cross reactivity to HERG (Kv11.1) and neuronal sodium channels (which was a problem for the early Pfizer compounds), a small molecule Kv1.3 blocker should also be selective over the very closely related Kv1-family channels Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6 and Kv1.7, which display a very high degree of homology in the intracellular part of the S5-P-S6 region, where most of the small molecule blockers bind. Correolide for example affects all Kv1-family channels with equivalent affinity, and by blocking Kv1.1 channels increased the peristaltic activity of the gastrointestinal tract [63,64]. So far, the only small molecule Kv1.3 blockers that exhibit degrees of selectivity that seem acceptable for development are PAP-1, which exhibits 23-fold selectivity over the Kv1.5 and 33- to 125-fold selectivity over the rest of the Kv1-family channels [35], and several of the Bionomics compounds like the example shown in Figure 2, which has been reported to exhibit 37-fold selectivity over Kv1.5 [58,65].…”