Criteria-based assessment of analgesic activity of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines derivatives based on dataexperimental studies

Abstract

BACKGROUND: An urgent task in pharmacology is to identify highly effective drugs with analgesic and anti-inflammatory activity. Heterocyclic cyanothioacetamide compounds are of considerable interest. Most authors evaluate the results of studies with separate private indicators of analgesic activity, and their comprehensive criterion assessment is insufficiently defined.

AIM: Development of a criterion assessment in the study of analgesic activity and the establishment of its generalized criteria for samples of chemical compounds of medicinal products.

MATERIALS AND METHODS: The experiments were performed on 390 male rats weighing 250–280 g in the laboratory of the Department of Fundamental and Clinical Pharmacology of St. Luke Lugansk State Medical University. Intact, control and reference (comparison group) groups of ten animals in each group were formed for each pharmacological test. In the intact group, the rats were unharmed. The control group received 2 mL of 0.9% sodium chloride solution intragastrically before each pharmacological test to establish analgesic activity. The reference group was injected with sodium metamizole at a dose of 7 mg/kg intragastrally once 1.5 h before modelling an acute pain reaction. Ten experimental groups were also formed, in which rats were injected with appropriate samples of new original studied derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridine intragastrically at a dose of 5 mg/kg 1.5 h before modelling acute pain syndrome. Tests for orofacial trigeminal pain, thermal immersion and hot plate were simulated. The indicators of the analgesic effect were the frequency of scratching movements in the orofacial trigeminal pain test and a statistically significant increase in the latent reaction period after the administration of the studied substances in the thermal immersion tests of the tail and hot plate.

RESULTS: The studied samples with ciphers AZ-023, AZ-331 and AZ-383 showed maximum analgesic activity. The proposed criterion of analgesic activity in the experimental groups receiving thienopyridine derivatives with the AZ-023 cipher, according to the results of three tests, was 50.1, exceeding the indicator in the comparison group by 42 times. The values of this criterion in the experimental groups that received new 1,4-dihydropyridine derivatives with laboratory ciphers AZ-331 and AZ-383 for preventive purposes were the maximum in this series of experiments (64.3 and 68.4), which is 53–57 times higher than that of sodium metamizole.

CONCLUSION: The methodology for assessing analgesic activity can be improved based on a criteria-based approach with the aggregation of particular indicators into an abstract model that allows quantifying the degree of analgesic activity. An integral criterion for the analgesic activity of cyanothioacetamide derivatives based on experimental data is proposed. In the future, the proposed approach can be used in studies of various analgesic samples.

Keywords

аnalgesic / anti-inflammatory agents / 1,4-dihydropyridine

References

[1] Khan MM, Khan S, Saigal S, Iqbal S. Recent developments in multicomponent synthesis of structurally diversifi ed tetrahydropyridines. RSC Adv. 2016;(6):42045–42061. doi: 10.1039/c6ra06767k

[2] Khan M.M., Khan S., Saigal S., Iqbal S. Recent developments in multicomponent synthesis of structurally diversifi ed tetrahydropyridines // RSC Adv. 2016. N 6. P. 42045–42061. doi: 10.1039/c6ra06767k

[3] Krivokolysko DS, Dotsenko VV, Bibik EY, et al. New 4-(2-Furyl)-1,4-dihydronicotinonitriles and 1,4,5,6-Tetrahydronicotinonitriles: synthesis, structure, and analgesic activity. Russian Journal of General Chemistry. 2021;91(9):1646–1660. EDN: GSRUOX doi: 10.1134/S1070363221090073

[4] Кривоколыско Д.С., Доценко В.В., Бибик Е.Ю., и др. Новые 4-(2-фурил)-1,4-дигидроникотинонитрилы и 1,4,5,6-тетрагидроникотинонитрилы: синтез, строение и анальгетическая активность // Журнал общей химии. 2021. Т. 91, № 9. С. 1359–1374. EDN: GSRUOX doi: 10.1134/S1070363221090073

[5] Krivokolysko DS, Bibik EYu, Samokish AA, et al. New hybrid molecules based on sulfur-containing nicotinonitriles: synthesis, analgesic activity in acetic acid-induced writhing test, and molecular docking studies. Russian Journal of Bioorganic Chemistry. 2022;48(3):628–635. EDN: GLHHRP doi: 10.1134/S1068162022030104

[6] Krivokolysko D.S., Bibik E.Y., Samokish A.A., et al. New hybrid molecules based on sulfur-containing nicotinonitriles: synthesis, analgesic activity in acetic acid-induced writhing test, and molecular docking studies // Russian Journal of Bioorganic Chemistry. 2022. Vol. 48, N 3. P. 628–635. EDN: GLHHRP doi: 10.1134/S1068162022030104

[7] Bibik IV, Pokrovskij MV, Bibik EYu, et al. Determination of the complex criterion of analgesic activity of new derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines in an experiment. Medical Newsletter of Vyatka. 2023;(3):37–44. (In Russ). EDN: VHJLJK doi: 10.24412/2220-7880-2023-3-37-45

[8] Бибик И.В., Покровский М.В., Бибик Е.Ю., и др. Определение комплексного критерия анальгетической активности новых производных конденсированных 3-аминотиено[2,3-b]пиридинов и 1,4-дигидропиридинов в эксперименте // Вятский медицинский вестник. 2023. № 3. С. 37–44. EDN: VHJLJK doi: 10.24412/2220-7880-2023-3-37-45

[9] Polosinov SA. Synthesis of integral evaluation criteria in decision-making tasks. In: XII All-Russian Meeting on Management Problems VSPU-2014. Moscow: V.A. Trapeznikov Institute of Management Problems, Russian Academy of Sciences; 2014; 2014 Jul 16–19; P. 7943–7954. (In Russ). EDN: SSMVUP

[10] Полосинов С.А. Синтез интегральных оценочных критериев в задачах принятия решений. В кн.: XII Всероссийское совещание по проблемам управления ВСПУ-2014. Москва: Институт проблем управления им. В.А. Трапезникова РАН, 2014; 16–19 июля 2014 г.; С. 7943–7954. EDN: SSMVUP

[11] Karas SI. Information bases of decision-making in medicine. Tomsk: Pechatnaja manufaktura; 2003. 146 р. (In Russ). EDN: RKANVX

[12] Карась С.И. Информационные основы принятия решений в медицине. Томск: Печатная мануфактура, 2003. 146 с. EDN: RKANVX

[13] Chajka AV, Cheretaev IV, Khusainov DR. Methods of experimental pre-clinical testing of analgesic effect of various factors on laboratory rats and mice. Uchenye zapiski Krymskogo federal’nogo universiteta im. V.I. Vernadskogo. Seriya «Biologiya, himiya». 2015;(1):161–173.

[14] Чайка А.В., Черетаев И.В., Хусаинов Д.Р. Методы экспериментального доклинического тестирования анальгетического действия различных факторов на лабораторных крысах и мышах // Ученые записки Крымского федерального университета им. В.И. Вернадского. Серия «Биология, химия». 2015. № 1. С. 161–173.

[15] Loktionova EV, Panacheva EV. The use of mathematical methods for pharmaceutical analysis. In: Collection of materials of the conference “Day of Science in KGMA”. Karaganda; 2008. Available from: https://articlekz.com/article/7753 (In Russ).

[16] Локтионова Е.В., Паначева Е.В. Использование математических методов для фармацевтического анализа. В кн.: Сборник материалов конференции «День науки в КГМА». Караганда, 2008. Режим доступа: https://articlekz.com/article/7753

[17] Budylina EA, Garkina IA, Danilov AM, Pylaikin SA. Approaches to the multicriteriality of complex systems. Molodoj uchenyj. 2013;(6):40–43. EDN: RHJUOR

[18] Будылина Е.А., Гарькина И.А., Данилов А.М., Пылайкин С.А. Подходы к многокритериальности сложных систем // Молодой ученый. 2013. № 6. С. 40–43. EDN: RHJUOR

[19] Kurochkina A, Kurochkina LG. Mathematics in the profession of a pharmacist. Prokudino; 2019. Available from: http://sar-ped-ob.ru/sites/default/files/raboti/092019/kurochkina_a._rabota_na_sayt.pdf (In Russ).

[20] Курочкина А., Курочкина Л.Г. Математика в профессии фармацевта. Прокудино, 2019. Режим доступа: http://sar-ped-ob.ru/sites/default/files/raboti/092019/kurochkina_a._rabota_na_sayt.pdf

[21] Loktionova NN, Filchakova KA. Application of mathematical research methods in medicine. Innovation Science. 2015;1(3):133–134. (In Russ). EDN: TMVRGJ

[22] Локтионова Н.Н., Фильчакова К.А. Применение математических методов исследования в медицине // Инновационная наука. 2015. Т. 1, № 3. С. 133–134. EDN: TMVRGJ

[23] Peskov K. Mathematical modeling: a new trend in pharmaceuticals. Remedium. 2013;(4):52–53. EDN: QACNFD

[24] Песков К. Математическое моделирование: новый тренд в фармацевтике // Ремедиум. 2013. № 4. С. 52–53. EDN: QACNFD

[25] Peskov KV. Mathematical modeling in drug development. Vestnik Roszdravnadzora. 2013;(1):57–60. EDN: PWWGTZ

[26] Песков К.В. Математическое моделирование при разработке лекарств // Вестник Росздравнадзора. 2013. № 1. С. 57–60. EDN: PWWGTZ

[27] Zubov NN, Umarov SZ, Bunin SA. Mathematical methods and models in pharmaceutical science and practice. Saint Petersburg: Izdatel’stvo Politehnicheskogo universiteta; 2008. 249 p. (In Russ). EDN: QLTDKZ

[28] Зубов Н.Н., Умаров С.З., Бунин С.А. Математические методы и модели в фармацевтической науке и практике. Санкт- Петербург: Издательство Политехнического университета, 2008. 249 с. EDN: QLTDKZ

[29] Semenova OS. Mathematical modeling in medicine. Byulleten’ medicinskih internet-konferencij. 2014;4(5):897. (In Russ).

[30] Семёнова О.С. Математическое моделирование в медицине // Бюллетень медицинских интернет-конференций. 2014. Т. 4, № 5. С. 897.

[31] Sokolov V, Stolbov L, Yakovleva T, Peskov K. Development of approaches to the description of complex physiological systems by the method of systemic pharmacological modeling to support the development of medicines [Internet]. 2020. Available from: https://dodo.inm.ras.ru/biomath-archive/presentationsXII/Sokolov.pdf (In Russ).

[32] Соколов В., Столбов Л., Яковлева Т., Песков К. Разработка подходов к описанию сложных физиологических систем методом системно-фармакологического моделирования для поддержания разработки лекарственных препаратов [интернет]. 2020. Доступ по ссылке: https://dodo.inm.ras.ru/biomath-archive/presentationsXII/Sokolov.pdf

[33] Serdyukova O. Research work. Methods of mathematical analysis in medicine [Internet]. 2012. Available from: https://pandia.ru/text/77/439/65064.php (In Russ).

[34] Сердюкова О. Исследовательская работа. Методы математического анализа в медицине [интернет]. 2012. Доступ по ссылке: https://pandia.ru/text/77/439/65064.php

[35] Gfeller D, Michielin O, Zoite V. Shaping the interaction landscape of bioactive molecules. Bioinformatics. 2013;29(23):3073–3079. doi: 10.1093/bioinformatics/btt540

[36] Gfeller D., Michielin O., Zoite V. Shaping the interaction landscape of bioactive molecules // Bioinformatics. 2013. Vol. 29, N 23. P. 3073–3079. doi: 10.1093/bioinformatics/btt540

[37] Mironov AN, editor. Guidelines for conducting preclinical studies of medicines. Moscow: Grif i K; 2012. 941 p. (In Russ). EDN: SDEWMP

[38] Руководство по проведению доклинических исследований лекарственных средств / под ред. А.Н. Миронова. Москва: Гриф и К. 2012. 941 с. EDN: SDEWMP

[39] Petri A, Sabin K. Visual statistics in medicine. Moscow: GEOTAR-Med, 2002. 144 p. (In Russ).

[40] Петри А., Сэбин К. Наглядная статистика в медицине. Москва: ГЭОТАР-Медиа, 2002. 144 с.

[41] https://sciencenow.ru/ [Internet]. What is a squared second in physics? Available from: https://sciencenow.ru/cto-takoe-sekunda-v-kvadrate-v-fizike/

[42] https://sciencenow.ru/ [интернет]. Что такое секунда в квадрате в физике? Доступ по ссылке: https://sciencenow.ru/cto-takoe-sekunda-v-kvadrate-v-fizike/

Funding

Минобрнаука РоссииMinistry of Education and Science of the Russian Federation(FREE-2023-0002)

RIGHTS & PERMISSIONS

Eco-Vector