1-(5-ACETYL-3-METHYL-6-PHENYL-5H-[1,2,4]TRIAZOLO [3,4-b][1,3,4]THIADIAZIN-7-YL)-ETHANONE: DOSE-DEPENDENCE OF ANALGESIC EFFECT, LACK OF OPIOIDERGIC MECHANISM OF ACTION, EFFECT ON BEHAVIORAL REACTIONS AND ACUTE TOXICITY

Abstract

Derivatives of 5,7-diacyl-3-H(alkyl)-6-aryl-5H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazine. Aim. To evaluate the dose dependence of the analgesic effect of the compound IFT_247, the participation of the opioidergic component in the mechanism of action of this compound, its influence on behavioral reactions in the open field test, and to determine acute toxicity. Materials and Methods. The compound IFT_247 was chosen as the object of research. 80 white outbred male mice were used in the study. Research on somatic pain was conducted using the "Hot Plate" test. Naloxone was used as a competitive opioid receptor blocker, and metamizole sodium was used as a comparison drug. Behavioral responses were studied in the open field test. Acute toxicity was determined in vivo according to the method of V.B. Prozorovsky. The results were processed using the STATISTICA 10.0 program. Results and Discussion. The lowest tested dose of compound IFT_247, 5 mg/kg, produced a weak analgesic effect at the trend level (34.9% increase). Increasing the dose to 15 mg/kg produced a greater effect (68.1% increase, p<0.01). The 25 mg dose effect was the largest (149.6% increase, p<0.001), and increasing the dose to 35 mg/kg did not increase it (135.9% increase, p<0.001). Therefore, the analgesic effect of the compound IFT_247 depends on the dose, and the maximum effective dose can be considered to be 25 mg/kg, it is this dose that was taken for the following experiments. Analysis of the data from the study of the opioidergic mechanism of the compound IFT_247 demonstrates that the opioid receptor blocker naloxone did not affect its analgesic effect. This compound per se increased hindpaw licking LP by an average of 54%. Against the background of the effect of naloxone, the LP of the nociceptive reaction increased by 72.8%, the differences with the indicator of the group of the studied compound per se differ at the level of the trend. For comparison, a similar experiment was performed with the classical analgesic-antipyretic sodium metamizole. The average increase in the LP nociceptive response during its use per se was 306.3%, and during the previous blockade of opioid receptors with naloxone - 204.4%, that is, it decreased on average by a third, and the median of the final latent time decreased by 2 times with almost the same initial value. Therefore, the opioidergic mechanism is not involved in the analgesic effect of the IFT_247 compound, however, the subtle neurochemical mechanism of the analgesic effect of the IFT_247 compound needs further clarification. In the open field test, no significant effect of the compound IFT_247 on the behavior of mice was found. The only significant difference was an increase in the number of boluses (p<0.05), however, the remaining indicators of emotional reactions and their vegetative accompaniment (grooming, urination) did not differ from the control values. Thus, the studied compound does not cause either a stimulating or depressing effect on the CNS. When determining the acute toxicity of the compound IFT_247, a dose of 2000 mg/kg did not cause a lethal effect in any mouse. Doses of 2500 and 3980 mg/kg caused the death of 1 animal, and a dose of 5010 mg/kg was lethal in all mice. Based on these results, the LD50 was calculated, which is 2840±340 mg/kg. Therefore, according to the results, the compound IFT_247 belongs to low-toxic substances (500 mg/kg < LD50 < 5000 mg/kg, toxicity class IV according to Noge and Sterner classification). Conclusions. The IFT_247 compound exerts a dose-dependent analgesic effect, the maximum effective dose being 25 mg/kg. Opioidergic influence is not involved in the mechanism of analgesic action of the compound. This compound does not cause changes in the behavior of mice in the open field test and belongs to the IV toxicity class - low-toxic substances.