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Bioinformation 2012The sodium "channelopathies" are the first among the ion channel diseases identified and have attracted widespread clinical and scientific interests. Human voltage gated...
The sodium "channelopathies" are the first among the ion channel diseases identified and have attracted widespread clinical and scientific interests. Human voltage gated sodium channels are sites of action of several antiarrhythmic drugs, local anesthetics and related antiepileptic drugs. The present study aims to optimize the activity of Disopyramide, by modification in its structures which may improve the drug action by reducing its side effects. Herein, we have selected Human voltage-gated sodium channel protein type 5 as a potent molecular target. Nearly eighty analogs of Disopyramide are designed and optimized. Thirty are selected for energy minimization using Discovery studio and the LigPrep 2.5. Prior to docking, the active sites of all the proteins are identified. The processing, optimization and minimization of all the proteins is done in Protein preparation wizard. The docking study is performed using the GLIDE. Finally top five ranked lead molecules with better dock scores are identified as having strong binding affinity to 2KAV protein than Disopyramide based on XP G scores. These five leads are further docked with other similar voltage gated sodium channel proteins (PDB IDs: 2KBI, 4DCK, 2L53 and 4DJC) and the best scoring analog with each protein is identified. Drug likeliness and comparative bioactivity analysis for all the analogs is done using QikProp 3.4. Results have shown that the top five lead molecules would have the potential to act as better drugs as compared to Disopyramide and would be of interest as promising starting point for designing compounds against various Sodium channelopathies.
PubMed: 23275710
DOI: 10.6026/97320630081139 -
British Journal of Pharmacology and... Dec 1963A quantitative comparison of the effects of quinidine, pronethalol and gamma-di-isopropylamino-alpha-phenyl-alpha-pyrid-2-ylbutyramide (disopyramide) has been made on...
A quantitative comparison of the effects of quinidine, pronethalol and gamma-di-isopropylamino-alpha-phenyl-alpha-pyrid-2-ylbutyramide (disopyramide) has been made on rabbit isolated atria. All three drugs raised the electrical threshold and reduced the contractions, the conduction velocity and the maximal frequency at which the atria would follow a stimulus. The descending order of potency was pronethalol, quinidine and disopyramide, but the range was small, pronethalol having about twice the activity of disopyramide. Both the new compounds affected intracellular potentials in the same way as quinidine, causing little change in the resting potential or duration of the action potential, but reducing the overshoot potential and slowing the rate of rise of the action potential. These results support the view that interference with depolarization is an essential feature of antifibrillatory activity.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Disopyramide; Electrophysiology; Ethanolamines; Heart; Heart Atria; Pharmacology; Quinidine; Rabbits; Research; Sympatholytics
PubMed: 14110747
DOI: 10.1111/j.1476-5381.1963.tb02015.x -
International Journal of Molecular... Jan 2021Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with...
In Silico Assessment of Class I Antiarrhythmic Drug Effects on -Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues.
Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.
Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Computer Simulation; Disopyramide; Heart Atria; Homeodomain Proteins; Humans; Mice; Propafenone; Quinidine; Transcription Factors; Homeobox Protein PITX2
PubMed: 33514068
DOI: 10.3390/ijms22031265 -
Bioorganic Chemistry May 2020A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly...
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
Topics: Acetamides; Animals; Anticonvulsants; Disopyramide; Dose-Response Relationship, Drug; Electroshock; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Molecular Structure; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Structure-Activity Relationship
PubMed: 32171994
DOI: 10.1016/j.bioorg.2020.103717 -
The Journal of Toxicological Sciences 2017In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we...
In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 ± 0.01 m/sec, 453 ± 10 msec and 361 ± 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and flecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1 spike amplitude reduction after the treatment of Na channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.
Topics: Arrhythmias, Cardiac; Calcium Channel Blockers; Cell Culture Techniques; Electric Stimulation; Heart Rate; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Sodium Channel Blockers
PubMed: 28321045
DOI: 10.2131/jts.42.183 -
British Journal of Pharmacology Jan 19931. Anti-acetylcholine effects of pilsicainide, flecainide, disopyramide and propafenone on the acetylcholine (ACh)-induced K+ current (IK.ACh) were examined in...
1. Anti-acetylcholine effects of pilsicainide, flecainide, disopyramide and propafenone on the acetylcholine (ACh)-induced K+ current (IK.ACh) were examined in dissociated guinea-pig atrial myocytes under whole-cell voltage clamp by the use of the 'concentration-clamp' technique. 2. The IK.ACh was activated with a latency of about 100 ms after 1 microM ACh application and desensitized to a steady-state level. The latent period and the time to peak response were shortened with increasing ACh concentration. 3. The values of half-maximal inhibition (IC50) on the peak and steady state responses were 25 and 25 microM for pilsicainide, 1.7 and 2.0 microM for disopyramide, 19 and 2.0 microM for flecainide and 0.7 and 0.2 microM for propafenone, respectively. 4. Pilsicainide and disopyramide increased the latent period and the time to peak of IK.ACh in a concentration-dependent manner. Flecainide and propafenone did not change the latent period, but shortened the time to peak and hastened the decay of IK.ACh in a voltage-independent manner. 5. The results suggest that the mechanisms underlying the anti-acetylcholine effect of antiarrhythmic drugs are different among these drugs: i.e., pilsicainide and disopyramide mainly block the muscarinic ACh receptors while flecainide and propafenone inhibit the K+ channel itself as open channel blockers.
Topics: Acetylcholine; Animals; Anti-Arrhythmia Agents; Disopyramide; Electric Conductivity; Flecainide; Guinea Pigs; Lidocaine; Male; Myocardium; Potassium; Potassium Channels; Propafenone
PubMed: 8428201
DOI: 10.1111/j.1476-5381.1993.tb13448.x -
British Journal of Pharmacology Sep 19871 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both...
1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of 0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis of first-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m infinity and h infinity. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in gNa and an increase in the time constant of inactivation (tau h). 5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.
Topics: Animals; Axonal Transport; Axons; Cesium; Decapodiformes; Disopyramide; Fluorides; In Vitro Techniques; Membrane Potentials
PubMed: 2444301
DOI: 10.1111/j.1476-5381.1987.tb11298.x -
Journal of Pharmacological Sciences Sep 2008Kv1.5 is considered to be a potential molecular target for treatment of atrial fibrillation or flutter. Disopyramide is widely used in the treatment of atrial flutter...
Kv1.5 is considered to be a potential molecular target for treatment of atrial fibrillation or flutter. Disopyramide is widely used in the treatment of atrial flutter and/or atrial fibrillation. The present study was undertaken to characterize the effects of disopyramide on currents mediated by Kv1.5 channels and to determine the putative binding site involved in the inhibitory effects of disopyramide. Experiments were carried out on wild-type and site directed mutated hKv1.5 channels expressed on HEK 293 cells using the patch-clamp technique. Disopyramide acting from the cytoplasmic side of the membrane produced blocking effects on Kv1.5 that exhibited several features typical of an open channel blocker. Ala-scanning mutagenesis of the Kv1.5 pore domain combined with macroscopic current analysis suggested that disopyramide interacted only with the Val512 residue that faces to the central cavity of the channel. Mutation of this key residue to Ala caused marked change in the IC(50) of disopyramide (22-fold). The single interaction between disopyramide and Val512 in the PVP region is able to change the mechanism of channel closure, reproducing the "foot-in-the-door" phenomenon.
Topics: Alanine; Anti-Arrhythmia Agents; Cell Line; Data Interpretation, Statistical; Disopyramide; Humans; Kv1.5 Potassium Channel; Mutagenesis; Patch-Clamp Techniques; Potassium Channel Blockers
PubMed: 18818480
DOI: 10.1254/jphs.08084fp -
Clinical Cardiology Jul 1987In vitro and in vivo electrophysiological studies have shown that propafenone could be classified as a class I antiarrhythmic agent. The aim of this study was to... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
In vitro and in vivo electrophysiological studies have shown that propafenone could be classified as a class I antiarrhythmic agent. The aim of this study was to investigate the short-term antiarrhythmic efficacy and safety of propafenone in 10 patients compared to disopyramide in a double-blind randomized protocol. Included patients suffered from ventricular arrhythmias with at least 60 ventricular premature beats (VPB) per hour refractory to at least two other antiarrhythmic agents. At the end of the control period and of the two treatment periods during which patients received either propafenone (300 mg three times a day) or disopyramide (200 mg three times a day), clinical examination, Holter recordings, electrocardiogram, and clinical laboratory tests were performed. The PR interval and the QRS interval were significantly increased with propafenone, but not with disopyramide. The cQT interval was not significantly changed by either propafenone or disopyramide. Heart rate was decreased with propafenone (p less than 0.05) with no change in the diurnal/nocturnal circadian ratio variation. Heart rate was significantly decreased with disopyramide only during the day. Five of nine patients in the propafenone group and two of nine patients in the disopyramide group showed a reduction in ventricular premature beats greater than 80%. Total resolution of severe arrhythmias (repetitive events) was seen in 5 of 8 patients with propafenone; 2 of 8 with disopyramide. Adverse events, when they occurred, were mild (visual disturbances, epigastric discomfort, changes in taste perception, transient atrioventricular block with propafenone, and photophobia with disopyramide), and did not require reduction or discontinuation of study drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Aged; Cardiac Complexes, Premature; Chronic Disease; Disopyramide; Double-Blind Method; Female; Heart Conduction System; Heart Rate; Humans; Male; Middle Aged; Propafenone; Random Allocation
PubMed: 2440632
DOI: 10.1002/clc.4960100707 -
Journal of Chromatography. A Oct 2017A method that combined on-line immunoextraction with high-performance affinity chromatography was developed to examine the binding of drugs with α-acid glycoprotein...
A method that combined on-line immunoextraction with high-performance affinity chromatography was developed to examine the binding of drugs with α-acid glycoprotein (AGP). Affinity microcolumns containing immobilized polyclonal anti-AGP antibodies were developed that had a capture efficiency of up to 98.4% for AGP and a binding capacity of 0.72nmol AGP when using a 20mm×2.1mm i.d. microcolumn. These microcolumns were employed in various formats to examine the binding of drugs to normal AGP and AGP that had been adsorbed from serum samples for patients with systemic lupus erythematosus (SLE). Drugs that were screened in zonal elution experiments for their overall binding to these types of AGP included chlorpromazine, disopyramide, imipramine, propranolol, and warfarin. Most of these drugs showed an increase in their binding to the AGP from SLE serum when compared to normal AGP (i.e., an increase of 13-76%); however, disopyramide gave a 21-25% decrease in retention when the same AGP samples were compared. Frontal analysis was used to further evaluate the binding of disopyramide and imipramine to these forms of AGP. Both drugs gave a good fit to a model that involved a combination of saturable and non-saturable interactions with AGP. Changes in the non-saturable interactions accounted for most of variations seen in the binding of disopyramide and imipramine with the AGP samples. The methods used in this study could be adapted for use in personalized medicine and the study of other proteins or drugs using aqueous mixtures or clinical samples.
Topics: Antibodies; Chlorpromazine; Chromatography, Affinity; Disopyramide; Drug Interactions; Humans; Imipramine; Orosomucoid; Pharmaceutical Preparations; Propranolol; Protein Binding; Warfarin
PubMed: 28886937
DOI: 10.1016/j.chroma.2017.08.073