Synthesis and pharmacological activity of various organic and inorganic salts of phenyl derivatives of imidazobenzimidazole

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.10.465

Abstract

Introduction: The creation of new opioid analgesics that are devoid of the main undesirable effects – euphoria, respiratory depression, tolerance – is an important task for the treatment of pain syndrome. Eighteen salts of 9-pyrrolidinoethyl-(1a), 9-piperidinoethyl-(1b), and 9-morpholinoethyl-2-(4-fluorophenyl)benzo[d]imidazo[1,2-a]imidazole (1c) were synthesized and tested for kappa agonist and analgesic activity.

Materials and Methods: Specific analgesic activity studies were conducted using models of nociceptive pain in the “Hot/Cold-plate” and ”Plantar Test” tests, and in neuropathic pain against the background of sciatic nerve ligation. The relationship between the physicochemical and pharmacological properties of the compounds was studied in silico using quantum chemistry methods and artificial neural network technology.

Results: The most active compound identified was 4-(2-(2-(4-fluorophenyl)-benzo[d]imidazo[1,2-a]imidazol-9-yl)ethyl)morpholine dihydrochloride (1c.2HCl). EC50, acute toxicity, and conditional therapeutic index values were calculated, which were 38.8 times superior to the kappa agonist U50488. It was established that compound 1c.2HCl exhibits a dose-dependent analgesic effect in the “Hot/Cold-plate” test, which is six times superior to that of butorphanol, maintaining a statistically significant effect for six hours in the “Plantar test” and without causing the formation of tolerance with a ten-day administration. In models of neuropathic pain syndrome, 1c.2HCl with a fourteen-day administration significantly reduced tactile and cold allodynia by three and 1.6 times, respectively, and was not inferior in activity to gabapentin. The kappa-opioidergic mechanism of the antinociceptive action of 1c.2HCl compound was confirmed. Quantum chemistry methods and artificial neural network technologies have shown that the high level of kappa-opioid agonist activity of hydrochlorides, in contrast to other salts, results in lower total energy production; therefore, there is a significant increase in energy during the formation of a salt supramolecular complex.

Conclusion: The most active compound was identified – 1c.2HCl, for which kappa-opioid activity in vitro and analgesic properties were revealed in various in vivo models. It has been shown that the compound does not cause the formation of tolerance and is not toxic.

Graphical Abstract

Keywords:

artificial neural networks, imidazobenzimidazole derivatives, kappa-opioid agonists, nociceptive and neuropathic pain, opioid analgesics, quantum chemical modeling

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Author Contribution

Olga N. Zhukovskaya, Institute of Physical and Organic Chemistry of the Southern Federal University

PhD in Chemical Sciences, Senior researcher at the Laboratory of Organic Synthesis, Institute of Physical and Organic Chemistry, Rostov-on-Don, Russia; e-mail: zhukowskaia.ol@yandex.ru; ORCID ID https://orcid.org/0000-0003-2485-2139. The author proposed the design of the structures, synthesized the compounds, studied their structure, and wrote the chemical part of text.

Natalya V. Eliseeva, Volgograd State Medical University

PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd; e-mail: nvkirillova@rambler.ru; ORCID ID https://orcid.org/0000-0002-2243-5326. The author was engaed in obtaining, analyzing and interpreting pharmacological data, editing the pharmacological part of the manuscript.

Pavel M. Vassiliev, Volgograd State Medical University

Doctor Habil. of Biological Sciences, Full Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd; e-mail: pvassiliev@mail.ru; ORCID ID https://orcid.org/0000-0002-8188-5052. The author was engaed in performing computational studies, analyzing and interpreting computational results, and editing the computational part of the manuscript.

Gleb V. Pridvorov, Volgograd State Medical University

PhD student, Assistant of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd; e-mail: gleb.pridvorov@gmail.com; ORCID ID https://orcid.org/0000-0002-8070-693X. The author was engaed in conducting experimental work and mathematical processing of the obtained data.

Olesya Yu. Grechko, Volgograd State Medical University

Doctor Habil. of Medical Sciences, Full Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd; e-mail: olesiagrechko@mail.ru; ORCID ID https://orcid.org/0000-0002-4184-4897. The author was engaed in obtaining, analyzing.

Anatoly S. Morkovnik, Institute of Physical and Organic Chemistry

Doctor Habil. of Chemical Sciences, Head of the Laboratory of Organic Synthesis, Institute of Physical and Organic Chemistry, Rostov-on-Don, Russia; e-mail: asmork@mail.ru; ORCID ID https://orcid.org/0000-0002-9182-6101. The author was engaged in editing the chemical part of the manuscript.

Alexander A. Spasov, Volgograd State Medical University

Doctor Habil. of Medical Sciences, Professor, Member of the Russian Academy of Sciences, Head of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd; e-mail: aspasov@mail.ru; ORCID ID https://orcid.org/0000-0002-7185-4826. The author proposed the concept and design of the manuscript and approved of the final version of the manuscript.

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Published

30-06-2024

How to Cite

Zhukovskaya ON, Eliseeva NV, Vassiliev PM, Pridvorov GV, Grechko OY, Morkovnik AS, Spasov AA (2024) Synthesis and pharmacological activity of various organic and inorganic salts of phenyl derivatives of imidazobenzimidazole. Research Results in Pharmacology 10(2): 119–133. https://doi.org/10.18413/rrpharmacology.10.465

Issue

Vol. 10 No. 2 (2024)

Section

Experimental Pharmacology

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Copyright (c) 2024 Olga N. Zhukovskaya, Natalya V. Eliseeva, Pavel M. Vassiliev, Gleb V. Pridvorov, Olesya Yu. Grechko, Anatoly S. Morkovnik, Alexander A. Spasov

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