Development of New Openers of ATP-Sensitive Potassium Channels of the Cell Membranes

TitleDevelopment of New Openers of ATP-Sensitive Potassium Channels of the Cell Membranes
Publication TypeJournal Article
Year of Publication2016
AuthorsStrutynskyi, RB, Strutynska, NA, Maximyuk, OP, Platonov, MO, Boyko, OM, Vasylchenko, OV, Fedyanovich, IM, Dosenko, VYe., Krishtal, OO
Short TitleNauka innov.
SectionResearch and Engineering Innovative Projects of the National Academy of Sciences of Ukraine
Two innovative libraries (413 cyclosulfamides and 709 orthopyridine sulfamides) of potential new openers of ATP-sensitive potassium channels of cell membranes were developed. It is shown experimentally that at least ten new original compounds have properties of pharmacological openers of the channels. Seven compounds, namely Z851154982, Z56762024, Z1269122570, Z31153162, Z45679561, Z756371174 and Z649723638, open channels of both types — sarcoplasmic as well as mitochondrial membranes: Simultaneously, Z734043408 compound is a potent activator of aforementioned channels of sarcolemmal membrane only. Z31197374 and Z666664306 compounds show the affinity onlyto КATP-channels of mitochondrial type. The results of the work can be used by pharmaceutical companies and scientific research institutes.
Keywordsglibenclamide, KATP-channels, mitochondria, new openers, vasodilation effects

1. Gorbas I.M. Risk factors for cardiovascular disease: prevalence and control. Medical portal «Health of Ukraine». Published 28/03/2015.
Access: [in Ukrainian].
2. Dudnik S. Cardiovascular disease in Ukraine: the forecasts - disappointing Medical Newspaper «Your Health», Cardiology, published 01/09/2015.
Access: [in Ukrainian].
3. Strutynskyi R., Mohort M., Yagupolskii L., Moibenko O. Flocalin - new domestic cardioprotectors. Visnyk farmakologii i farmacii (Journal of Pharmacology and Phar macy). 2010, 3: 44-56 [in Ukrainian].
4. Barsukevich V., Basalay M., Sanchez J., Mrochek A., Whittle J., Ackland G.L., Gourine A.V., Gourine A. Dis tinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning. Basic. Res. Cardiol. 2015, 110(1): 452-462.
5. Rana A., Goyal N., Ahlawat A., Jamwal S., Reddy B.V., Sharma S. Mechanisms involved in attenuated cardioprotective role of ischemic preconditioning in metabolic disorders. Perfusion. 2015, 30(2): 94-105.
6. Strutyns'kyi R.B. The vasodilation effects of flokalin, a fluorine-containing K(ATP) channel opener. Fiziol. Zh. 2010, 56(4): 59-65 [in Ukrainian].
7. Ishizaka H., Kuo L. Acidosis-induced coronary arteriolar dilation is mediated by ATP-sensitive potassium chan nels in vascular smooth muscle. Circ. Res. 1996, 78(1): 50-57.
8. Strutyns'kyi R.B., Neshcheret O.P., Tumanovs'ka L.V., Rovenets' R.A., Moibenko O.O. Cardioprotective effects of flokalin in experiments in vivo: influence on hemo dy namic and myocardial lesions in ischemia-reperfusion. Fiziol. Zh. 2009, 55(5): 9-16 [in Ukrainian].
9. Strutyns'kyi R.B., Kotsiuruba A.V., Neshcheret O.P., Shysh A.M., Rovenets' R.A., Moibenko O.O. Cardioprotective effects of activation of ATP-sensitive potassium channels in experiments in vivo: influence on blood biochemical parameters following ischemia-reperfusion of the myocardium. Fiziol. Zh. 2009, 55(6): 12-9 [in Ukrainian].
10. Wakahara N., Katoh H., Yaguchi Y., Uehara A., Satoh H., Terada H., Fujise Y., Hayashi H. Difference in the cardioprotective mechanisms between Ischemic preconditioning and pharmacological preconditioning by diazoxide in rat hearts. Circ. J. 2004, 68(2): 156-162.
11. Strutyns'kyi R.B., Kotsiuruba A.V., Rovenets' R.A., Strutyn s'ka N.A., Iagupols'kyi Iu.L., Sagach V.F., Moibenko O.O. Biochemical mechanisms of the cardioprotective effect of the K(ATP) channels opener flocalin (medicinal form) in ischemia-reperfusion of myocardium. Fiziol. Zh. 2013, 59(4): 16-27 [in Ukrainian].
12. Voitychuk O.I., Strutynskyi R.B., Yagupolskii L.М., Tinker A., Moibenko O.O., Shuba Y.M. Sarcolemmal cardiac KATP channels as a target for the cardioprotective effects of the fluorine-containing pinacidil analogue flocalin. Brit. J. Pharmacol. 2011, 162(3): 701-711.
13. Strutyns'kyi R.B., Rovenets' R.A., Moibenko O.O. Me chanisms of cardioprotective action domestic opener of the KATP-channels flocalin. Tavricheskiy mediko-biologicheskiy vestnik. 2012, 15(3). pt. 2: 226-229 [in Ukrainian].
14. Moibenko О.О., Strutynskyi R.B., Yagupolskii L.M., Mohort M.A. Creation and preparation to apply the new do mestic cardioprotective drug - fluorine-containing activator of ATP-dependent potassium channel Flocalin. Nauka innov. (Science and Innovation). 2006, 2(4): 77-82 [in Ukrainian].
15. Strutyns'kyi R.B., Pyvovar S.M., Tumanovs'ka L.V., Moibenko O.O. Cardioprotective effects of flokalin: relative role of activation of sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels. Fiziol. Zh. 2008, 54(6): 15-23 [in Ukrainian].
16. Strutyns'ka N.A., Strutyns'kyi R.B., Chorna S.V., Semenykhina O.M., Mys' L.A., Moibenko O.O., Sahach V.F. New fluorine-containing openers of ATP-sensitive potassium channels flokalin and tioflokalin inhibit calcium-induced mitochondrial pore opening in rat hearts. Fiziol Zh. 2013, 59(6): 3-11 [in Ukrainian].
17. Alizadeh A.M., Faghihi M., Khori V., Sohanaki H., Po urkhalili K., Mohammadghasemi F., Mohsenikia M. Oxytocin protects cardiomyocytes from apoptosis induced by ischemia-reperfusion in rat heart: role of mitochondrial ATP-dependent potassium channel and permeability transition pore. Peptides. 2012, 36(1): 71-77.
18. Strutyns'kyi R.B., Nagibin V.S., Strutyns'ka N.A., Ianchii O.R., Moibenko O.O. Influence of flocalin on development of apoptosis and necrosis at anoxia-reoxygen- ation of culture rats neonatal cardiomyocytes. Fiziol. Zh. 2013, 59(3): 3-9 [in Ukrainian].
19. Das B., Sarkar C. Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and anti infarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model. Pol. J. Pharmacol. 2003, 55(5): 771-786.
20. Strutyns'kyi R.B., Rovenets' R.A., Neshcheret O.P., Tu manovs'ka L.V., Boichuk T.M., Dzhuran B.V., Moibenko O.O. Effect of medical form of flocalin on the course of myocardial reperfusion injury. Fiziol. Zh. 2011, 57(1): 55-65 [in Ukrainian].
21. Suryapranata H. Coronary haemodynamics and vaso dila tory profile of a potassium channel opener in patients with coronary artery disease. Eur. Heart J. 1993, 14: 16-21.
22. Friedel H.A., Brogden R.N. Pinacidil: a review of its pharmacodynamic and pharmacokinetic properties, and thera peutic potential in the treatment of hypertension. Drugs. 1990, 39: 929-967.
23. Jahandir A., Terzic A. KATP channel therapeutics at the bedsise. J. Mol. Cell. Cardiology. 2005, 39: 99-112.
24. Strutynsk'kyi R. B., Moibenko O.O. Modeling of K+ATP channel activity in normotensive and hypertensive animals. Fiziol. Zh. 2000, 46(6): 54-60 [in Ukrainian].
25. Bhatnagar A., Bolli R. Modulation of KATP channels to protect the ischemic myocardium: Clinical implications. Exp. Clin. Cardiol. 1999, 4(1): 20-22.
26. Strutyns'kyi R.B., Moibenko O.O., Iahupol's'kyi L.M. The vasomotor effects of new fluorine-containing synthetic activators of ATP-dependent potassium channels. Fiziol. Zh. 2000, 46(4): 17-23 [in Ukrainian].
27. Pyvovar S.M., Strutyns'kyi R.B., Iagupol's'kyii L.M., Moibenko O.O. Study of the mechanism of action of novel fluoro-containing analogs of diazoxide on the vascular tonus. Fiziol. Zh. 2004, 50(2): 27-33 [in Ukrainian].
28. Yagupolskii L.М., Maletina I.I., Petko K.I., Moibenko A.A., Strutinsky R.B., Pivovar S.N., Ye.V. Tarasova. Difluoromethoxy- and trifluoromethoxy-containing analogs of potassium chanels activator diazoxide. J. Org. and Pharmac. Chem. 2008, 6(22): 37-47.
29. Strutyns'kyi R.B. Investigation influence of new activators ATP-dependent potassium channels on cardiac function and vasomotor reactions in normal and pathological conditions. PhD (pathophysiol.) Kyiv, 2002 [in Ukrainian].
30. Moybenko O.O., Strutynskyi R.B., Yagupolskii L.M., Mohort M.A., Shalamai A.S. Organization of industrial production of Flokalin - new myotropic spasmolytic and car dioprotector. Nauka innov. (Science and Innovation). 2009, 5(1): 80-84 [in Ukrainian].
31. Patent of Ukraine №99508. Krishtal О.A., Maximyuk О.P., Strutynskyi R.B., Moibenko O.O., Platonov M.О., Boiko О.М., Vasylchenko О.В. Method of creating new activators of ATP-dependent potassium channels of cell membranes [in Ukrainian].
32. Chuprina A., Lukin O., Demoiseaux R., Buzko A., Shivanyuk A. Drug-and lead-likeness, target class, and molecular diversity analysis of 7.9 million commercially available organic compounds provided by 29 suppliers. J. Chem. Inf. Model. 2010, 50(4): 470-479.
33. Sahach V.F., Vavilova H.L., Strutyns'ka N.A., Rudyk O.V. Aging-related increase of sensitivity of the mitochondrial permeability transition pore to inductors in the rat heart. Fiziol. Zh. 2004, 50(2): 49-63 [ in Ukrainian].
34. Quayle J.M., Nelson M.T., Standen N.B. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol. Rev. 1997, 77(4): 1165-1232.
35. Strutynskyi R.B., Moybenko O.O., Chebanov V.A., Gorobets N.Yu. Modeling of production industrial process of the drug flocalin and search of its optimally effective dose for treatment of heart diseases. Nauka innov. (Science and Innovation). 2013, 9(1): 55-63 [in Ukrainian].