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)

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.

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“…At the same time, none of the proposed methods and their combinations provide guaranteed protection against ischemia-reperfusion injury, in connection with which the search and selection of innovative and promising compounds and preparations of this orientation continue. Preclinical studies at the systemic (Korokin et al, 2014;Peresypkina et al, 2016;Yakushev et al, 2016), cellular (Danilenko et al, 2016;Kravchenko et al, 2016;Kalmikov et al, 2018), and molecular (Bogus et al, 2018;Dzhimak et al, 2018;Soldativ et al, 2018) levels, including specific activity (Gumanova et al, 2007;Denisyuk et al, 2016;Danilenko, 2018) and toxicology studies (Kolesnichenko et al, 2018) in conjunction with bioequivalence studies )Kalmikov et al, 2018(, therapeutic equivalence and effectiveness (Avdeeva et al, 2016) are an integral part of the research of innovative drugs.…”