2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1H-indole hydrochloride (SS-68): Antiarrhythmic and Cardioprotective Activity and Its Molecular Mechanisms of Action (Part II)

Authors

  • Saida K. Bogus Kuban State Medical University
  • Pavel A. Galenko-Yaroshevsky Kuban State Medical University
  • Konstantin F. Suzdalev Southern Federal University
  • Galina V. Sukoyan International Research Centre for Biophysics and Introduction of New Biomedical Technologies
  • Valery G. Abushkevich Kuban State Medical University
  • Vladislav O. Soldatov Belgorod State National Research University

DOI:

https://doi.org/10.3897/rrpharmacology.4.30329

Abstract

Introduction. In previous studies on different animal models, it was shown that compound N-(N-butylpyrrolidine)-2-phenylindole hydrochloride (SS-68) has a broad antiarrhythmic activity. The molecular mechanisms of the pharmacological action of SS-68 were chosen as the focus for this study.

Materials and methods. The study of the molecular basis of the pharmacological action of SS-68 was based on 1) molecular docking with the determination of the affinity constant for κ1-opioid receptors; 2) recording the fluorescence of a culture of cardiomyocytes with the determination of the effect of SS-68 on ionic homeostasis; 3) determining the negative chronotropic action in vitro; 4) studying the effect of SS-68 on the transmembrane ion currents of isolated unidentified neurons of the large pond snail (Lymnaeastagnalis), orb snail (Planorbariuscorneus) and rat hippocampal neuron cultures.

Results. 1) In experiments using molecular docking, the affinity of SS-68 for κ1-opioid receptors is significantly higher than that of butorphanol, but lower than that of (-)-U-50.488; 2) In spontaneously excited preparations of the right atrium, SS-68 causes an irreversible negative chronotropic effect. In experiments on atrial myocardium in rats, SS-68 is capable of demonstrating the ability to block M2 and M3-cholinergic receptors; 3) When studying the effects on cardiac myocyte ion currents, it was shown that SS-68 has moderate Na+, K+ and Ca2+ – blocking activity; 4) In the study of isolated neurons, it was shown that SS-68 influences the electrophysiology of neurocytes in a dose-dependent manner.

Discussion. The study of the molecular basis of the action of SS-68 showed that this compound has a pleiotropic multitarget effect, which consists of, at least, the effect on Na+, Ca2+ and K+-homeostasis of cardiomyocytes and neurons, M2-, M3-cholinergic receptors, and κ1-opioid receptors.

Conclusion. From the point of view of molecular pharmacology, SS-68 can be attributed to an antiarrhythmic drug with a mixed type of action.

Keywords:

arrhythmias, antiarrhythmic drugs, SS-68, isolated hippocampal neurons, great pond snail neurons

Author Contribution

Saida K. Bogus, Kuban State Medical University

PhD in Medicine, a cardiologist of municipal budget health care institution Regional Clinical Hospital № 2 of the Krasnodar Ministry of Healthcare. Under the supervision of the scientific consultant, the author conducted an analysis of Russian and foreign literature sources, defined the goals and objectives of the study, as well as methods to reach them, independently conducted a targeted screening of most indole derivatives and took a direct part in an in-depth preclinical study of the antiarrhythmic and antianginal activity of SS-68.

Pavel A. Galenko-Yaroshevsky, Kuban State Medical University

Corresponding member of The Russian Academy of Medical Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Pharmacology. The author provided consultations on the planning, design and implementation of the experiment.

Konstantin F. Suzdalev, Southern Federal University

PhD in Chemistry, Associate Professor, The Department of Chemistry. The author was engaed in chemical synthesis of compound SS-68 and a wide range of other indole-based candidate molecules for screening their antiarrhythmic activity.

Galina V. Sukoyan, International Research Centre for Biophysics and Introduction of New Biomedical Technologies

Doctor of Medical Sciences, Professor, research officer. The author participated in the experimental study of molecular basis of SS-68 action.

Valery G. Abushkevich, Kuban State Medical University

Doctor of Medical Sciences, Professor, Professor of the Normal Physiology Department. The author participated in the experimental study of molecular basis of SS-68 action.

Vladislav O. Soldatov, Belgorod State National Research University

Post-graduate student, The Department of Pharmacology and Clinical Pharmacology. The author participated in the experimental study of molecular basis of SS-68 action.

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Published

30-09-2018

How to Cite

Bogus SK, Galenko-Yaroshevsky PA, Suzdalev KF, Sukoyan GV, Abushkevich VG, Soldatov VO (2018) 2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1H-indole hydrochloride (SS-68): Antiarrhythmic and Cardioprotective Activity and Its Molecular Mechanisms of Action (Part II). Research Results in Pharmacology 4(3): 73–86. https://doi.org/10.3897/rrpharmacology.4.30329

Issue

Vol. 4 No. 3 (2018)

Section

Review article

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