Effects of new antiarrhythmic agent SS-68 on excitation conduction, electrical activity in Purkinje fibers and pulmonary veins: Assessment of safety and side effects risk

Abstract

The compound SS-68 has been selected among numerous new derivatives of indole and demonstrated antiarrhythmic effects in animal models. The present study concerns several aspects of SS-68 safety and efficacy as a potential antiarrhythmic drug. The first estimation of atrioventricular conduction in mammalian heart under SS-68 has been carried out; effects of SS-68 in Purkinje fibers and myocardium of pulmonary veins have been investigated. The drug weakly affects cardiac atrioventricular conduction: only high concentrations of SS-68 (≥10 μmol/L) significantly decrease this parameter. Also, the drug weakly affects Purkinje fibers automaticity, but effectively alters action potential waveform in Purkinje fibers in a concentration-dependent manner. SS-68 (0.1-100 μmol/L) failed to induce any early or delayed afterdepolarizations in Purkinje fibers both in basal conditions and under provocation of proarrhythmic activity by norepinephrine (NE). Moreover, 10 μmol/L SS-68 suppressed NE-induced extra-beats and rapid firing in Purkinje fibers. In pulmonary veins only high concentrations of SS-68 significantly increased action potential duration, while lower concentrations (0.1-1 μmol/L) were ineffective. Also, 0.1-100 μmol/L SS-68 was unable to elicit arrhythmogenic alternations of action potential waveform in pulmonary veins. In conclusion, SS-68 has no proarrhythmic effects, such as afterdepolarizations or abnormal automaticity in used experimental models.

A Catalytic One-Pot Synthesis of Indolyl Cyclobutanones

“…1 H NMR (500 MHz, CDCl 3 ):  = 7.25-7.24 (m, 4 H), 7.20-7.17 (m, 3 H), 7.00 (m, 1 H), 6.97-6.95 (s, 1 H), 5…”

“…Due to the extremely high number of natural bioactive compounds containing an indole unit, 1 a wide number of chemoselective syntheses and functionalizations of this heterocycle have been exploited. 2 In particular, many investigations were focused on the identification of new and specific therapeutic agents for the treatment of several human diseases such as glaucoma, 3 hypertension, 4 depression, 5 Alzheimer's disease, 6 cardiovascular diseases, 7 and viral infections. 8 A number of strained cyclobutyl-and cyclopropylindole derivatives have aroused significant interest, not only for their pharmacological properties but, above all, for their usefulness in drug-receptor affinity studies.…”

Catalytic Tandem Friedel–Crafts Alkylation/C4–C3 Ring-Contraction Reaction: An Efficient Route for the Synthesis of Indolyl Cyclopropanecarbaldehydes and Ketones

“…In particular, a large number of biologically active indole compounds have been identified to date . Of those, over 200 have also been approved as therapeutic agents for the treatment of different human diseases such as glaucoma, hypertension, depression, and Alzheimer’s disease and as anticancer, antiarrhythmic, and antiviral drugs or are undergoing clinical trials . Notably, constrained cyclopropylindoles have been investigated as lead compounds for the development of various bioactive molecules (Scheme ), such as HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs), mineralocorticoid receptor antagonists (MCRAs), serotonin reuptake inhibitors, and Polo-like kinase 4 (Plk4) inhibitors .…”