Potent Potassium Channel Research Articles

Empagliflozin significantly attenuates sotalol-induced QTc prolongation in rats.

Sotalol is a class III antiarrhythmic drug commonly used in various arrhythmia treatments. However, due to its potent potassium channel inhibition, it can prolong the QT interval and lead to malignant arrhythmias. Empagliflozin is an inhibitor of sodium‑glucose cotransporter 2 (SGLT2) and has a positive effect on cardiovascular outcomes. Since the effect of empagliflozin on the activation of potassium channels is unknown, there is no recommendation regarding the coadministration of these drugs. The study aimed to evaluate the possible protective effects of empagliflozin on sotalol‑induced QT prolongation. We randomized 24 rats into 4 groups. The control group received only physiological saline, the EMPA group, empagliflozin; the SOT group, sotalol; and the EMPA+SOT group, empagliflozin and sotalol. PR and QT intervals and heart rates were measured under anesthesia at baseline and at 1, 2, and 3 hours in lead II. In the SOT group, the QT and QTc intervals as well as T‑wave duration were statistically longer, whereas heart rates were lower than in the control group (P <0.001 for all parameters). Empagliflozin ameliorated sotalol‑induced QT and QTc prolongation in the EMPA+SOT group. The QT interval, T‑wave duration, and QTc interval were shorter, and the heart rate was greater than in the SOT group (P <0.001, P = 0.002, P <0.001, and P <0.001, respectively). Empagliflozin significantly ameliorates sotalol‑induced QT prolongation and could be used safely with sotalol in clinical practice. Future clinical trials might recommend the routine use of empagliflozin to prevent QTc prolongation in diabetic patients receiving sotalol.

The ShK fold as an efficient scaffold for potent potassium channel blockade and other functions

The ShK fold as an efficient scaffold for potent potassium channel blockade and other functions

Design, synthesis and evaluation of substituted piperidine based KCNQ openers as novel antiepileptic agents

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.

Formulation and Evaluation of Microsponge Based Nicorandil Sustained Released Tablet

The aim of the present work was to develop once-daily sustained release microsponges formulations of Nicorandil, a potent potassium channel opener used in cardiovascular diseases and it has low oral bioavailability (70%) and half-life 1 h. So, it is good candidate for sustained release formulations based on microsponge technology. The microsponges were prepared by using quasi-emulsion solvent diffusion method. Scanning Electron Microscopy (SEM) revealed that the microsponges of nicorandil with Eudragit - RSPO and HPMC K100M were smooth, porous, glossy and discrete spherical. The actual drug content and encapsulation efficiency of batch M1 to M9 were obtained in range of 62.05 ± 0.31 to 80.69 ± 0.43 and 64.41 ± 1.71 to 70.58 ± 1.12, respectively. The microsponges formulations were subjected to in-vitro release studies and the results were evaluated kinetically and statically. The best fitted model was found to be Korsmeyer - Peppas model (R2 = 0.9992) for M6 batch. The ‘n’ value for Korsmeyer - Peppas model was between 0.5 and 1.0 which is indicative of non-Fickian diffusion. Statistical analysis using ANOVA yielded a p value of 0.572 for all the formulations, indicating that there was no significant difference among them.

Design, synthesis and computational evaluation of a novel intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl) benzamide as potential potassium channel blocker in epileptic paroxysmal seizures

The narrow therapeutic range and limited pharmacokinetics of available Antiepileptic drugs (AEDs) have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule targeting voltage gated potassium channels anticipated to have superior pharmacological than existing potassium channel blockers. The compound was synthesized by reacting (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4] benzodiazepine5,11(10H,11aH)-dione with 4-(Trifluoromethyl) benzoic acid (C8H5F3O2) in DMF and N,N′-dicyclohexylcarbodiimide (DCC) which lead to the formation of an intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl)benzamide with a perfect crystalline structure. The structure of the compound was characterized by FTIR, 1H NMR and 13C NMR analysis. The crystal structure is confirmed by single crystal X-ray diffraction analysis. The Structure-Activity Relationship (SAR) studies revealed that substituent of fluoro or trifluoromethyl moiety into the compound had a great effect on the biological activity in comparison to clinically used drugs. Employing computational approaches the compound was further tested for its affinity against potassium protein structure by molecular docking in addition, bioactivity and ADMET properties were predicted through computer aided programs.

Unintentional 4-Aminopyridine Overdose in a Multiple Sclerosis Patient

Objective: To discuss the clinical presentation and treatment of a 4-aminopyridine overdose resulting from a pharmacy prescription compounding error. Case Summary: A 55-year-old female with a 12-year history of multiple sclerosis is reintroduced to immediate-release 4-aminopydrine for symptom management. Four hours after the second dose, she is admitted to the emergency room with altered mental status, pulmonary edema, and seizures progressing to status epilepticus. She is intubated and managed with benzodiazepines followed by a propofol infusion. After 5 days she is discharged to home. Laboratory analysis of the capsules detected 127 mg of 4-aminopyridine, yet the prescription label indicated the contents as 12.5 mg capsules, to be taken twice a day. Discussion: There are 14 cases of previously published 4-aminopyridine toxicity in the literature. Four of those cases are due to pharmacy compounding errors. This case presents with typical and anticipated symptomatology such as acute delirium, cognitive changes, speech changes, elevated blood pressure, tachycardia, seizures, and status epilepticus. However, this case is unique in that the patient also presented with pulmonary edema, a finding not mentioned in the previous 14 cases. These adverse drug events are due to the neurotransmitter release induced through potassium channel blockade afforded by 4-aminopyridine when ingested in excessive amounts. In the context of adverse drug events, the 4-aminopyridine overdose as the causal link for the clinical findings in this case as determined by the Naranjo probability scale is ranked as definite. Conclusion: 4-Aminopyridine is a potent potassium (Kv) channel blocker and is accepted as a therapeutic agent for multiple sclerosis patients. In excess, 4-aminopyridine can produce significant adverse neurological effects most notable being status epilepticus. To date, no 4-aminopyridine overdose case reported has ended in death. Caution is advised to those pharmacists who provide compounding services.

ChemInform Abstract: Design and Efficient Synthesis of A‐278637 Derivatives as Potential Potassium Channel Opener.

AbstractFollowing a promising scaffold, a series of novel thieno[3,2‐b]quinoline derivatives (IV) are synthesized by one‐pot three‐component reaction under solvent‐ and catalyst‐free conditions.

Design and efficient synthesis of A-278637 derivatives as potential potassium channel opener

A series of thieno[3,2-b]quinoline derivatives designed based on A-278637 scaffold, were synthesized efficiently via one-pot three-component reaction under solvent-free and catalyst-free conditions. This work provides a new compound library with potential biological activity for biomedical screening.

206 The time course of new T-wave ECG descriptors following single and double dose administration of Sotalol in healthy subjects

The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation. 12-lead digital ECG Holter were recorded in 38 healthy subjects (27 males, mean age=27.4±8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l Sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using 3 biomarker categories: conventional ECG time intervals, Principal Component Analysis (PCA) analysis on the T-wave, and fully automatic biomarkers computed from a mathematical model of the T-wave. QT interval was significantly prolonged starting 1h20 minutes after drug dosing with 160 mg and 1h 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T-wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes. The duration of manual QT and automatic surrogate QT were strongly correlated (R2=0.92, p<0.001). The Bland & Altman plot revealed a non-stationary systematic bias (bias =26.5ms ±1.96*SD = 16ms). Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies.

The time course of new T-wave ECG descriptors following single- and double-dose administration of sotalol in healthy subjects.

The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation. Twelve-lead digital ECG Holter was recorded in 38 healthy subjects (27 males, mean age = 27.4 + or - 8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using three biomarker categories: conventional ECG time intervals, principal component analysis (PCA) analysis on the T wave, and fully automatic biomarkers computed from a mathematical model of the T wave. QT interval was significantly prolonged starting 1 hour 20 minutes after drug dosing with 160 mg and 1 hour 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes. The duration of manual QT and automatic surrogate QT were strongly correlated (R(2) = 0.92, P < 0.001). The Bland and Altman plot revealed a nonstationary systematic bias (bias = 26.5 ms + or - 1.96*SD = 16 ms). Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies.

Potassium Transport in Corynebacterium glutamicum Is Facilitated by the Putative Channel Protein CglK, Which Is Essential for pH Homeostasis and Growth at Acidic pH

We studied the requirement for potassium and for potassium transport activity for the biotechnologically important bacterium Corynebacterium glutamicum, which is used for large-scale production of amino acids. Different from many other bacteria, at alkaline or neutral pH, C. glutamicum is able to grow without the addition of potassium, resulting in very low cytoplasmic potassium concentrations. In contrast, at acidic pH, the ability for growth was found to depend on the presence of K+. For the first time, we provide experimental evidence that a potential potassium channel (CglK) acts as the major potassium uptake system in a bacterium and proved CglK's function directly in its natural membrane environment. A full-length CglK protein and a separate soluble protein harboring the RCK domain can be translated from the cglK gene, and both are essential for full CglK functionality. As a reason for potassium-dependent growth limitation at acidic pH, we identified the impaired capacity for internal pH homeostasis, which depends on the availability and internal accumulation of potassium. Potassium uptake via CglK was found to be relevant for major physiological processes, like the activity of the respiratory chain, and to be crucial for maintenance of the internal pH, as well as for the adjustment of the membrane potential in C. glutamicum.

ChemInform Abstract: The Synthesis and Biological Evaluation of a Range of Novel Functionalized Benzopyrans as Potential Potassium Channel Activators.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The synthesis and biological evaluation of a range of novel functionalised benzopyrans as potential potassium channel activators

A range of novel benzopyrans have been synthesised and biologically evaluated for K(ATP) channel activity employing cromakalim 1 as a benchmark K(ATP) channel opener. Although the compounds that were evaluated demonstrated a reduced ability to relax phenylephrine stimulated rat thoracic tissue, we provide evidence that benzopyrans 7a-h may be operating via an alternative mechanism than ATP-sensitive K(+) channel activity.

Synthesis of 9‐[1‐Benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl] perhydro‐1,8‐acridinediones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones

Abstractmagnified imageTricyclic dihydropyridines like ZM244085 are potential KATP channel openers. In this study 3‐cyanophenyl ring of ZM244085 was replaced with imidazolyl ring. So, 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones (5d‐f) were synthesized from 2‐alkylsulfonyl‐1‐benzyl‐5‐formylimidazole (4d‐f) and cyclohexane‐1,3‐dione according to classical Hantzch synthesis as potential potassium channel modulators.

1,4‐ and 2,4‐Substituted‐1,2,3‐triazoles as Potential Potassium Channel Activators. Part 7.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Analogs of a potent maxi-K potassium channel opener with an improved inhibitory profile toward cytochrome P450 isozymes

Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of 1 with a better inhibitory profile toward the CYP2C9 isozyme, the two acidic sites were chemically modified independently to generate a number of analogs. These analogs were evaluated as maxi-K channel openers in vitro using Xenopus laevis oocytes expressing cloned hSlo maxi-K channels. Compounds 15, 17, and 19 showed potent activity as maxi-K channel openers and were further evaluated for inhibition of the activity of the CYP2C9 isozyme. Compounds 17 and 19 showed diminished inhibitory potency against 2C9 and also against a panel of other more common CYP isozymes.

1,4- and 2,4-substituted-1,2,3-triazoles as potential potassium channel activators. VII

New 1,4- and 2,4-substituted 1,2,3-triazole derivatives were synthesized and tested as potential BK Ca channel openers, as a part of a research program, which hypothesizes a pharmacophoric structure containing the 1,2,3-triazole ring. The structure–activity relationships were studied introducing some structural changes concerning molecular geometry and the presence of a hydrogen bond donor as a primary amino group and a phenolic or alcoholic hydroxy function. The compounds were prepared by nucleophilic substitution on the 1,2,3-triazole ring and by 1,3-dipolar cycloaddition of azides to selected alkynes and to phenylacetone. The new compounds tested on rat aortic rings did not exhibit any significant vasorelaxing activity.

Titanium Tetraisopropoxide Catalyzed Synthesis of Base‐Sensitive Cyanoguanidine Analogs

The synthesis of base‐sensitive cyanoguanidine analogs of potent potassium channel openers was accomplished in two steps by converting the thiourea to a carbodiimide followed by Ti(OiPr)4 catalyzed addition of cyanamide in dichloromethane.

Graphical Abstracts

Synth. Commun. 2005, 35, 1 TITANIUM TETRAISOPROPOXIDE Catalyzed Synthesis of Base‐Sensitive Cyanoguanidine Analogs John K. Lynch, Peggy Huang, and Hao Bai Neurological and Urological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA The synthesis of base‐sensitive cyanoguanidine analogs of potent potassium channel openers was accomplished in two steps by converting the thiourea to a carbodiimide followed by Ti(OiPr)4 catalyzed addition of cyanamide in dichloromethane.