A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 microM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for ventricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.
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http://dx.doi.org/10.1021/jm00074a017 | DOI Listing |
CPT Pharmacometrics Syst Pharmacol
January 2025
Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Sotalol, a class III antiarrhythmic agent, is used to maintain sinus rhythm in patients with atrial fibrillation or atrial flutter (AFIB/AFL). Despite its efficacy, sotalol's use is limited by its potential to cause life-threatening ventricular arrhythmias due to QT interval prolongation. Traditionally, sotalol administration required hospitalization to monitor these risks.
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Department of Cardiothoracic Surgery, Ningbo Medical Center Lihuili Hospital of Ningbo University, No. 57, Xingning Rd, Ningbo City 315041, Zhejiang Province, China.
Doxorubicin (DOX) is a widely used antitumor drug; however, its use is limited by the risk of serious cardiotoxicity. Dehydroevodiamine (DHE) is a quinazoline alkaloid which has antiarrhythmic effects. The aim of this study was to investigate the protective effect of DHE on doxorubicin-induced cardiotoxicity (DIC) and its potential mechanism.
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Department of Emergency and Trauma Center, Nanchang First Hospital, Nanchang, Jiangxi, China.
Introduction: Depression is a prevalent and significant psychological consequence of traumatic brain injury (TBI). Ferroptosis, an iron-dependent form of regulated cell death, exacerbates the neurological damage associated with TBI. This study investigates whether nicorandil, a potassium channel opener with nitrate-like properties known for its antioxidative and neuroprotective effects, can mitigate depression-like behaviors following TBI by modulating ferroptosis.
View Article and Find Full Text PDFNat Commun
December 2024
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses.
View Article and Find Full Text PDFOpen Vet J
November 2024
Department of Molecular Biotechnology, Central Laboratory Unit, University Nacional Hermilio Valdizán, Huánuco, Perú.
Background: The limited and detailed literature on total intravenous anesthesia (TIVA), as well as the clinical indications for unilateral ovariectomy in llamas, are not well-defined. Therefore, it is necessary to understand the anesthetic events and the surgical intervention in this species.
Aim: The objective of this study was to evaluate the intraoperative physiological and clinical parameters in llamas undergoing unilateral ovariectomy, under three protocols of TIVA.
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