Neuronal K v 7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K v 7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K v 7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K v 7 channels, whereas its Renantiomer was a negative modulator. By contrast, at the K v 7.1 and the large conductance Ca 2ϩ -activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA A receptors (␣ 1  2 ␥ 2s and ␣ 2  2 ␥ 2s ) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S-and R-forms exhibited opposing effects on neuronal K v 7 channel subtypes allowed us to assess the potential role of K v 7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K v 7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.
WHAT IS ALREADY KNOWN • During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP). • In vitro testing has shown that most opioids can block the cardiac potassium channels. • This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. WHAT THIS PAPER ADDS • This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. • Neither morphine nor tramadol doses are associated with the QT interval length. AIMS During recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether‐a‐go‐go related gene (hERG) channels that are known to underlie cardiac repolarizing IKr current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro. METHODS One hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross‐sectional study. The QTc was estimated from a 12‐lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels. RESULTS There were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R2 = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R2 = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms1/2 (95% CI 2–19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low‐affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC50 = 171 µM oxycodone). CONCLUSIONS Among patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.
K(v)7 channels are unique among K(+) channels, since four out of the five channel subtypes have well-documented roles in the development of human diseases. They have distinct physiological functions in the heart and in the nervous system, which can be ascribed to their voltage-gating properties. The K(v)7 channels also lend themselves to pharmacological modulation, and synthetic openers as well as blockers of the channels, regulating neuronal excitability, have existed even before the K(v)7 channels were identified by cloning. In the present review we give an account on the focused efforts to develop selective modulators, openers as well as blockers, of the K(v)7 channel subtypes, which have been undertaken during recent years, along with a discussion of the K(v)7 ion channel physiology and therapeutic indications for modulators of the neuronal K(v)7 channels.
Effective screening of large compound libraries in ion channel drug discovery requires the development of new electrophysiological techniques with substantially increased throughputs compared to the conventional patch clamp technique. Sophion Bioscience is aiming to meet this challenge by developing two lines of automated patch clamp products, a traditional pipette-based system called Apatchi-1, and a silicon chip-based system QPatch. The degree of automation spans from semi-automation (Apatchi-1) where a trained technician interacts with the system in a limited way, to a complete automation (QPatch 96) where the system works continuously and unattended until screening of a full compound library is completed. The performance of the systems range from medium to high throughputs.
Large-conductance Ca 21 -activated K 1 channels (BK, K Ca 1.1, MaxiK) are important regulators of urinary bladder function and may be an attractive therapeutic target in bladder disorders. In this study, we established a high-throughput fluorometric imaging plate reader-based screening assay for BK channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC 50 value of 11.0 6 1.4 mM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization was achieved in manual whole-cell and inside-out patch-clamp studies in human embryonic kidney 293 cells expressing hBK channels: NS19504 caused distinct activation from a concentration of 0.3 and 10 mM NS19504 left-shifted the voltage activation curve by 60 mV. Furthermore, whole-cell recording showed that NS19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 mM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 mM) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K 1 concentration consistent with a K 1 channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels in urinary bladder function. The pharmacologic profile of NS19504 indicates that this compound may have the potential to reduce nonvoiding contractions associated with spontaneous bladder overactivity while having a minimal effect on normal voiding.
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