We previously described an integrated in vitro liability assay for seizure, a new approach methodology (NAM) to reduce toxicity due to central nervous system (CNS) liability in drug discovery and development. Here we report the development of structure activity relationships (SAR) to guide drug design away from this liability. SAR test compounds were selected from the Enamine REadily AccesibLe (REAL) database using pharmacophore features and similarity to previous test compounds (amoxapine, diphenhydramine, quetiapine, 4-AP, linopirdine) or to ion channel positive reference compounds (bepridil, NS1619, quinidine, verapamil, XE991). These 88 compounds (10 parent compounds and 78 structurally related derivatives) were screened by automated electrophysiology in cell lines expressing human KV2.1, NaV1.2, the α1β2γ2 GABAA or α4β2 nicotinic receptors to generate IC50 values. Across all 4 ion channels, the derivative compounds exhibited increased, equivalent or reduced potency compared with the parent compounds, providing a complex and rich dataset for SAR. Regarding individual pharmacophoric features, statistical analysis identified 12 features significantly associated with activity at the α4β2 nicotinic receptor; 4 of these were also significantly associated with activity at KV2.1. Selected parent compounds (amoxapine, diphenhydramine, quetiapine) and structural analogues were screened for seizure-like activity in human induced pluripotent stem cell neurons using microelectrode array. The seizure-like phenotype was altered with the derivatives, as expected from the respective ion channel IC50 values. These data provide insight into specific substructures associated with seizure-like drug toxicity, offering the opportunity to avoid CNS liability in the development of novel compounds, saving time, money, and resources.

KCNT1 channels are important targets in a variety of conditions, especially childhood epilepsies associated with activating mutations. Growing interest in this target has driven the discovery of KCNT1 channel modulators to serve as probes and leads for the development of novel therapeutics. Early pharmacological modulators such as quinidine, bepridil, and clofilium found through drug repurposing were generally limited by poor selectivity, low potency, and safety concerns, restricting their clinical potential. Structure-guided virtual screening, high-throughput screening, and systematic optimization have identified a suite of new KCNT1 modulators with more favorable pharmacological properties than existing in vitro probes identified through drug repurposing. This review provides an overview of the peer-reviewed literature describing chemotypes with structural features that enhance potency and selectivity compared to earlier KCNT1 modulators. Also discussed are structure-activity relationship (SAR) studies that have enabled the rational optimization of molecules to enhance overall drug-like properties. Together, these insights provide a foundation for the rational design of next generation KCNT1-targeted therapies. Progress in this field has been tremendous, and the chemical diversity of small molecule KCNT1 inhibitors has grown rapidly. While KCNT1 activators are rarer, progress has been made in this area as well.

This study evaluates virtual cardiac populations for preclinical assessment of drug-induced QT interval prolongation and arrhythmic risk. Traditional predictions often rely on small, healthy cohorts, excluding vulnerable populations. Using computational models of realistic heart anatomies and electrophysiology, we generated a virtual cohort of 512 subjects across healthy and diseased hearts (heart failure, dilated and hypertrophic cardiomyopathy, ischaemia, and myocardial infarction). We assessed QT prolongation and arrhythmic events following administration of moxifloxacin (benchmark antibiotic) and contraindicated drugs including quinidine, bepridil, and flecainide. Patients with heart failure, hypertrophic and dilated cardiomyopathy showed greater QT prolongation to moxifloxacin, unlike ischaemia and myocardial infarction, which resembled healthy subjects. Females exhibited consistently higher QT prolongation than males. Contraindicated drugs markedly increased arrhythmia risk in populations with heart failure, dilated and hypertrophic cardiomyopathy, and ischaemia, frequently leading to lethal arrhythmias such as Torsades des Pointes or ventricular fibrillation, particularly in females. These findings demonstrate that computational models capture variability in drug response across pathologies and sexes, offering a predictive framework for preclinical safety evaluations and supporting safer, more personalized drug development strategies.

Bepridil are often administered after catheter ablation (CA) in patients with persistent atrial fibrillation (AF); however, it is unclear for how long it should be continued. We administered hybrid therapy consisting of CA and bepridil to 130 patients with persistent AF and left atrial (LA) enlargement (volume index > 48 ml/m2). After 2 months of hybrid therapy, bepridil discontinuation was attempted. All patients underwent echocardiography 6 months after CA. We investigated the relationship between the duration of bepridil administration and the recurrence of AF after bepridil discontinuation. After excluding patients who were unable to maintain sinus rhythm during bepridil administration (n = 18), and those who disagreed to bepridil discontinuation (n = 17), 95 patients were divided into the short-term continuation (bepridil discontinued for < 6 months [median 3 months] after CA [n = 63]), and long-term continuation (bepridil discontinued for > 6 months [median 11.4 months] after CA [n = 32]) groups. During the mean follow-up period of 28 ± 15 months, the groups showed a similar incidence of recurrent AF after bepridil discontinuation. In the long-term continuation group, 13 patients had recurrence, with 8 (62%) cases occurring within 4 months after discontinuation. A multivariate Cox regression analysis revealed that left atrial (LA) reverse remodeling (> 15% decrease in LA volume index at 6 months) was an independent predictor of recurrent AF after CA (p < 0.01). Long-term bepridil administration after CA did not affect the recurrence of AF after discontinuation. The assessment of LA reverse remodeling may be useful for decision-making regarding the discontinuation of antiarrhythmic drugs after CA.

Topological indices are effective tools for modeling and predicting the molecular structure and physicochemical properties of medications, eliminating the need for lengthy laboratory procedures. Topological indices offer the benefit of acting as fundamental numerical indicators in models related to quantitative structure-property relationships (QSPR) and quantitative structure-activity relationships (QSAR). In this research, we investigate degree-based topological indices (TIs) that serve as molecular descriptors for the QSPR analysis of antiviral medications such as Favipiravir, Sertraline, Chloroquine, Ribavirin, Bepridil, Clomifene, Galidesivir, Nilotinib, and Brincidofovir, which affect the interactions between viruses and human proteins. We examine both linear and multilinear QSPR models to analyze the connections between different physical and chemical properties including molecular polarizability (MP), Log P, molecular refractivity (MR), and molecular weight (MW) and the numerical values associated with these drugs. Our results indicate a strong correlation between the topological indices of these antiviral medications and their physical and chemical characteristics.

Dronedarone (DRO) is an antiarrhythmic drug that should be used under close supervision, and therapeutic drug monitoring (TDM) may be one of the tools supporting pharmacotherapy. The aim of our study was to develop an economical HPLC method for determining DRO and its active metabolite debutyldronedarone (DBD) in human plasma. An HPLC isocratic system with a manual injector was applied. The separation was performed on a Supelcosil LC-CN column (150 × 4.6 mm, 5 µm) at an ambient temperature. The mobile phase was a mixture of CH3OH:CH3CN:H2O:0.5 M KH2PO4 (170:85:237.2:7.8 (v/v)) + 0.1 mL 85% H3PO4 pumped at a flow rate of 1.8 mL/min. The UV detection was set at λ = 290 nm. A methyl tert-butyl ether was used for the extraction from a 0.4 mL alkalized plasma sample. The analytes were eluted at retention times of 4.0 min, 5.2 min and 6.0 min for DBD, internal standard bepridil and DRO, respectively. The method was calibrated in the range of 10-1000 ng/mL for both DRO and DBD. The adequate specificity, accuracy and precision were demonstrated in accordance with EMA guidelines, i.e., ≤15% (≤20% for the LLOQ), which ensures the reliability of the measurements. This method can be recommended for laboratories with basic HPLC equipment for TDM, adherence assessments and even in PK studies during chronic DRO therapy.

Calcium (Ca[2+]) is a universal signaling cation with a prominent role as second messenger in many different plant processes, including sexual reproduction. However, there is much less knowledge about the involvement of Ca[2+] during in vitro embryogenesis processes. In this work we performed a study of Ca[2+] levels during the different stages of microspore embryogenesis in Brassica napus, with special attention to how Ca[2+] can influence the occurrence of different embryogenic structures with different embryogenic potential. We also performed a pharmacological study to modulate Ca[2+] homeostasis during different stages of the process, using a series of Ca[2+]-altering chemicals (BAPTA-AM, bepridil, chlorpromazine, cyclopiazonic acid, EGTA, inositol 1,4,5-trisphosphate, ionophore A23187, W-7). This study shows that Ca[2+] increase can be considered as an early marker of induction of microspore embryogenesis. Besides, Ca[2+] levels are highly dynamic during microspore embryogenesis, influencing the final embryo yield. Increase of either extracellular or intracellular Ca[2+] levels improves embryo yield without altering the proportion of highly embryogenic structures formed, which suggests that elevated Ca[2+] levels increase the amount of microspores reaching the minimum Ca[2+] threshold required for embryogenesis induction. Conversely, inhibition of Ca[2+] uptake or signaling results in reduced embryogenic response. This allows to modulate embryo yield within a functional range, with lower and upper Ca[2+] thresholds beyond which embryo yield is reduced. There seems to be a relationship between Ca[2+] levels and embryo differentiation.

Atrial fibrillation (AF) is the most common cause of tachycardia-induced cardiomyopathy (TIC). A 75-year-old woman was referred to our hospital for catheter ablation for persistent AF. On admission, transthoracic echocardiography (TTE) revealed diffuse left ventricular (LV) hypokinesis, which was suspected to be due to TIC. Catheter ablation was performed on the fifth day of hospitalization, and Torsade de Pointes (TdP) appeared on the sixth day. The serum concentration of bepridil and potassium was below the reference level. An electrocardiogram revealed marked QT prolongation, giant-negative T waves, and T-wave alternans on the seventh day of hospitalization. Cardiac magnetic resonance imaging with no contrast indicated diffuse mild LV hypokinesis, mild prolonged native T1, and no evidence of myocardial edema at T2. Coronary angiography revealed normal coronary arteries, and the ergonovine stress test results were negative. The results for five long QT syndrome susceptibility genes, including the three major genes, were negative. Subsequently, QT prolongation, giant-negative T waves, and LV dysfunction improved without treatment. This case report highlights the importance of risk management for AF patients with TIC scheduled for catheter ablation and carefully evaluating the risks of QT prolongation. Moreover, patients with TIC can experience marked QT prolongation and TdP during the perioperative period of catheter ablation. Therefore, caution should be required.