Novel 1,4-Dihydropyridine Derivatives as Potential Agents with Analgesic Activity IN Orofacial Trigeminal Pain Test: Experimental Preclinical Randomized Trial

Abstract

Background. In the majority of cases, contemporary pharmacological correction mainly focuses on the most effective analgesia. Therefore, the search for and research into new analgesic drugs are a priority in modern pharmacology.Objective — to establish the level of analgesic activity in eight novel heterocyclic compounds of 1,4-dihydropyridine derivatives synthesized in a classic test of orofacial trigeminal pain in animal experiments.Methods. An experimental preclinical randomized trial of the analgesic activity in 1,4-dihydropyridine derivatives was carried out. The experiment was conducted on 100 white male outbred rats in the laboratory of the Fundamental and Clinical Pharmacology Department, St. Luke Lugansk State Medical University, Lugansk People’s Republic. Novel 1,4-dihydropyridine derivatives were preliminarily investigated in a virtual biological screening by means of Swiss Target Prediction tool (Swiss Institute of Bioinformatics, Switzerland). The laboratory animals were divided into a control group (rats were exposed to acute pain syndrome by injecting 0.1 ml of 5% formalin solution into the vibrissae area without pharmacological correction), a comparison group (rats which received metamizole sodium (OOO Farmstandard) at a dose of 7 mg/kg 1.5 hour prior to acute pain syndrome modeling in the vibrissae area), and eight experimental groups (1.5 hours before formalin administration, novel 1,4-dihydropyridine derivatives under study at a dose of 5 mg/ kg were intragastrically injected). 10, 15 and 20 minutes after simulating acute pain, the number of scratching movements of the forelegs around orofacial region per minute was counted. Statistical processing of the results involved methods of mathematical statistics for quantitative variability and was carried out using Statistica 12.5 (IBM, USA).Results. Animals treated with 1,4-dihydropyridine derivatives d02-133 and d02-172 under the experimental conditions showed a significant (13–21 times) decrease in scratching movements frequency by the 10th minute of observation in comparison with the control group. By 15th minute, the analgesic activity of the cyanothioacetamide derivatives increased 14 and 11 times as compared to these indicators of the reference group. After 20 minutes, the analgesic activity of these compounds in terms of inhibiting nociceptive impulses, as compared to the control group, was also high, as the number of scratching movements in the vibrissae area in animals of these experimental groups was 8–9 times lower than in control group. The orofacial trigeminal pain test detected the most exhibited analgesic activity in novel cyanothioacetamide derivatives d02-139, d02-133, and d02-172, which appeared to be higher than that of metamizole sodium.Conclusion. It was found that novel original derivatives of 1,4-dihydropyridine showed a high degree of analgesic activity.

Keywords

• pain syndrome
• 1,4-dihydropyridine derivatives
• analgesic activity
• cyanothioacetamide
• anti-inflammatory activity