Diverse analgesic effects of novel benzimidazole derivatives

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Abstract

BACKGROUND: The development of novel analgesics is a critical priority due to the high prevalence of pain-related pathologies and the limitations of current treatments, which are often associated with undesirable side effects.

AIM: This study aimed to evaluate the analgesic properties of new imidazobenzimidazole (BIF-70 and BIF-72) derivatives through in vivo testing, compare their efficacy with previously studied compounds, and assess potential aversive effects.

MATERIALS AND METHODS: Experiments were conducted on mature rats sourced from the Rappolovo nursery (Leningrad Region). Analgesic activity was assessed using models of somatic, inflammatory, and neurogenic pain, following guidelines for preclinical studies. The animals were divided into 3 groups. Analgesic efficacy was tested using the Plantar Test. Acute inflammation was induced via the formalin hyperalgesia model. Neurogenic pain was modeled through sciatic nerve injury. Aversive effects were evaluated using the conditioned place avoidance test. Statistical analysis was performed using two-factor ANOVA.

RESULTS: The compounds demonstrated high analgesic activity, comparable to morphine. BIF-70 exhibited activity in both phases of inflammation, surpassing butorphanol in the first phase. BIF-72 showed no activity in the first phase but outperformed butorphanol in the second phase. In the neurogenic pain model Both compounds were less effective than gabapentin but comparable to morphine. In addition, BIF-70 induced a euphoric effect, increasing the time spent in the chamber associated with its administration. In contrast, BIF-72 showed no aversive or rewarding effects.

CONCLUSIONS: The study identified new analgesics with efficacy comparable to classical drugs in certain models. Notably, these compounds lacked the aversive effects typically associated with kappa-opioid agonists, highlighting their potential as promising therapeutic candidates.

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About the authors

Gleb V. Pridvorov

Volgograd State Medical University; Kirov Military Medical Academy

Email: gleb.pridvorov@gmail.com
ORCID iD: 0000-0002-8070-693X
SPIN-code: 7998-0743

Lecturer of the Department of Pharmacology, Kirov Military Medical Academy; assistant of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Ministry of Health of the Russian Federation

Russian Federation, Volgograd; Saint Petersburg

Alexander A. Spasov

Volgograd State Medical University

Email: aspasov@mail.ru
ORCID iD: 0000-0002-7185-4826
SPIN-code: 8777-1303

MD, Dr. Sci. (Medicine), Professor, Academician of the Russian Academy of Sciences, Head of the Department of Pharmacology and Bioinformatics

Russian Federation, Volgograd

Vyacheslav P. Ganapolsky

Kirov Military Medical Academy; North-Western State Medical University named after I.I. Mechnikov

Author for correspondence.
Email: ganvp@mail.ru
ORCID iD: 0000-0001-7685-5126
SPIN-code: 9872-8841

MD, Dr. Sci. (Medicine), Associate Professor, Acting Head of the Department of Pharmacology, Kirov Military Medical Academy; Professor of the Department of Pharmacology nd Pharmacy, North-Western State Medical University named after I.I. Mechnikov, Ministry of Health of the Russian Federation

Russian Federation, Saint Petersburg; Saint Petersburg

Anastasiya D. Dulimova

Volgograd State Medical University

Email: bellochka0805@mail.ru

student

Russian Federation, Volgograd

Olga Yu. Mukha

Volgograd State Medical University

Email: olay.myha14@gmail.com
ORCID iD: 0000-0002-0429-905X
SPIN-code: 2610-9280

Laboratory Technician of the Department of Pharmacology and Bioinformatics

Russian Federation, Volgograd

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Supplementary files

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2. Fig. 1. Comparison of relative changes in latency period for test compounds and reference drug. All test compounds showed statistically significant differences compared to the control group.

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3. Fig. 2. Changes in pain response counts in phase I and phase II. Relative values are shown: *statistically significant differences compared to the control group; #statistically significant differences compared to the reference drug. Data for the reference drug and RU-1205 were obtained from [3].

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4. Fig. 3. Changes in pain (a) and thermal (b) sensitivity at different stages of the study under the influence of test compounds. *Statistically significant differences compared to the control group on the corresponding day; #statistically significant differences compared to the reference drug on the corresponding day.

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5. Fig. 4. Changes in duration of animal presence in different chambers of the apparatus on day 1 and day 10 of training following administration of compound BIF-70 (а) or of compound BIF-72 (b). *Statistically significant differences between the indicated groups (Two-way ANOVA, p <0.05).

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6. Fig. 5. Changes in duration of animal presence in different chambers of the apparatus on day 1 and day 10 of training following administration of U-50,488, a classic kappa-opioid receptor agonist with pronounced aversive effects [22]. *Statistically significant differences between the indicated groups (Mann–Whitney U test, p <0.05).

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