Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

  • P. A. Virych Taras Shevchenko National University of Kyiv
  • O. V. Shelyuk Taras Shevchenko National University of Kyiv
  • T. A. Kabanova Taras Shevchenko National University of Kyiv
  • O. I. Khalimova O. V. Bogatsky Physico-Chemical Institute
  • V. S. Martynyuk Taras Shevchenko National University of Kyiv
  • V. I. Pavlovsky O. V. Bogatsky Physico-Chemical Institute
  • S. A. Andronati O. V. Bogatsky Physico-Chemical Institute
Keywords: 3-substituted 1, 4-benzodiazepines, bradykinin, kinin-kallikrein system, maximal normalized rate


The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM), gadolinium (300 μM) and 2-aminoethyl diphenylborinate (0.1 μM). The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn) of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal normalized rate of contraction and relaxation of carbachol- and potential-induced smooth muscle contraction. Based on the results and previous investigations, the MX-1775 is a potential blocker of kinin B2-receptors. Effects obtained for other compounds require additional research. 


Alves, F., Oliva, M., & Miranda, A. (2015). Conformational and biological properties of Bauhinia bauhinioides kallikrein inhibitor fragments with bradykinin-like activities. Journal of Peptide Science, 21(6), 495–500.
Baron, R., Binder, A., & Wasner, G. (2010). Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. The Lancet Neurology, 9(8), 807–819.
Bencze, M., Behuliak, M., Vavřínová, A., & Zicha, J. (2015). Broad-range TRP channel inhibitors (2-APB, flufenamic acid, SKF-96365) affect differently contraction of resistance and conduit femoral arteries of rat. European Journal of Pharmacology, 765(15), 533–540.
Bergson, P., Lipkind, G., Lee, S., Duban, M., & Hanck, D. (2011). Verapamil block of T-type calcium channels. Molecular Pharmacology, 79(3), 411–419.
Bon, R., & Beech, D. (2013). In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels – mirage or pot of gold? British Journal of Pharmacology, 170(3), 459–474.
Burdyga, T., & Kosterin, S. (1991). Kinetic analysis of smooth muscle relaxation. General Physiology and Biophysics, 10, 589–598.
Calixto, J., & Medeiros, Y. (1992). Bradykinin-induced biphasic response in the rat isolated stomach fundus: Functional evidence for a novel bradykinin receptor. Life Sciences, 50(7), PL47-PL52.
Chan, S., & Rudd, J. (2006). Role of bradykinin B2 receptors in the modulation of the peristaltic reflex of the guinea pig isolated ileum. European Journal of Pharmacology, 539, 108–115.
Choi, S., Park, D. Y., Yeum, C. H., Chang, I. Y., You, H. J., Park, C. G., Kim, M. Y., Kong, I. D., So, I., Kim, K. W., & Jun, J. Y. (2006). Bradykinin modulates pacemaker currents through bradykinin B2 receptors in cultured interstitial cells of Cajal from the murine small intestine. British Journal of Pharmacology, 148(7), 918–926.
Dziadulewicz, E., Brown, M., Dunstan, A., Lee, W., Said, N., & Garratt, P. (1999). The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold. Bioorganic and Medicinal Chemistry Letters, 9(3), 463–468.
Fattori, D., Rossi, C., Fincham, C. I., Caciagli, V., Catrambone, F., D’Andrea, P., Felicetti, P., Gensini, M., Marastoni, E., Nannicini, R., Paris, M., Terracciano, R., Bressan, A., Giuliani, S., Maggi, C. A., Meini, S., Valenti, C., & Quartara, L. (2007). Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides. Journal of Medicinal Chemistry, 50(3), 550–565.
Gierthmuhlen, J., Binder, A., & Baron, R. (2014). Mechanism-based treatment in complex regional pain syndromes. Nature Reviews Neurology, 10(9), 518–528.
Hall, J. (1997). Bradykinin receptors. General Pharmacology: The Vascular System, 28(1), 1-6.
Jaiswal, A., Kumar, S., Enjamoori, R., Seth, S., Dinda, A., & Maulik, S. (2010). Peripheral benzodiazepine receptor ligand Ro5-4864 inhibits isoprenaline-induced cardiac hypertrophy in rats. European Journal of Pharmacology 644, 146–153.
Kam, Y., Ro, J., Kim, H., & Choo, H. (2005). Antagonistic effects of novel non-peptide chlorobenzhydryl piperazine compounds on contractile response to bradykinin in the guinea-pig ileum. European Journal of Pharmacology, 523, 143–150.
Ludwig, J., & Baron, R. (2004). Complex regional pain syndrome: An inflammatory pain condition? Drug Discovery Today: Disease Mechanisms, 4(1), 449–455.
Malasics, А., Boda, D., Valiskó, M., Henderson, D., & Gillespie, D. (2010). Simulations of calcium channel block by trivalent cations: Gd3+ competes with permeant ions for the selectivity filter. Biochimica et Biophysica Acta – Biomembranes, 1798(11), 2013–2021.
Marcon, R., Claudino, R., Dutra, R., Bento, A., Schmidt, E., Bouzon, Z., Sordi, R., Morais, R., Pesquero, J., & Calixto, J. (2013). Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: The role of tight junctions and intestinal homeostasis. British Journal of Pharmacology, 168(2), 389–402.
Meini, S., Cucchi, P., Bellucci, F., Catalani, C., Giuliani, S., Santicioli, P., & Maggi, C. (2007). Comparative antagonist pharmacology at the native mouse bradykinin B2 receptor: Radioligand binding and smooth muscle contractility studies. British Journal of Pharmacology, 150(3), 313–320.
Persona, K., Madej, K., Knihnicki, P., & Piekoszewski, W. (2015). Analytical methodologies for the determination of benzodiazepines in biological samples. Journal of Pharmaceutical and Biomedical Analysis, 239(10), 239–264.
Prado, G., Taylor, L., Zhou, X., Ricupero, D., Mierke, D., & Polgar, P. (2002). Mechanisms regulating the expression, self-maintenance, and signaling-function of the bradykinin B2 and B1 receptors. Journal of Cellular Physiology, 193, 275–286.
Reddy, D., Ballante, F., Zhou, N., & Marshall, G. (2017). Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors. European Journal of Medicinal Chemistry, 127, 531–553.
Seidlmayer, L., Kuhn, J., Berbner, A., Arias-Loza, P. A., Williams, T., Kaspar, M., Czolbe, M., Kwong, J. Q., Molkentin, J. D., Heinze, K. G., Dedkova, E. N., & Ritter, O. (2016). Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes. Cardiovascular Research, 112(1), 491–501.
Stadnicki, A. (2011). Intestinal tissue kallikrein–kinin system in inflammatory Bowel disease. Inflammatory Bowel Diseases, 17(2), 645–654.
Virych, P., Sheljuk, O., Kabanova, T., Halimova, O., Martynjuk, V., Pavlovs’kyj, V., & Andronati, S. (2017). Vplyv 2-arylamino-1,2-dygidro-3N-1,4-benzdiazenip-2-ioniv na bradykinin-indukovane skorochennja gladen’kyh m’jaziv. Regulatory Mechanism in Biosystems, 8(1), 30–35 (in Ukrainian).
Virych, P., Shelyuk, O., Kabanova, T., Khalimova, E., Martynyuk, V., Pavlovsky, I., & Andronati, S. (2017). Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction. Ukrainian Biochemical Journal, 89(1), 31–37.
Zhang, X., Brovkovych, V., Zhang, Y., Tan, F., & Skidgel, R. (2015). Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling. Cell Signalling, 27(1), 90–103.
How to Cite
Virych, P., Shelyuk, O., Kabanova, T., Khalimova, O., Martynyuk, V., Pavlovsky, V., & Andronati, S. (2017). Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers. Regulatory Mechanisms in Biosystems, 8(2), 224-230. https://doi.org/https://doi.org/10.15421/021735

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