Search

Selective kappa-opioid receptor (KOR) agonists are considered a promising group of substances for developing opioid analgesics characterised with an original mechanism of action without the risk of respiratory depression and drug addiction. Previous studies identified a fluorophenyl derivative of imidazo[1,2-a]benzimidazole (RU-1205) with a KOR-based mechanism of analgesic action established in in vitro and in vivo experiments.The aim of the study was to assess the effect of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole dihydrochloride on the level of DNA damage in rats after a single subcutaneous injection.Materials and methods. The study was conducted in adult white outbred laboratory rats of both sexes. DNA damage was estimated using the comet assay. The study involved a single subcutaneous injection of an aqueous solution of RU-1205 in three doses: 1, 10, and 100 mg/kg. The authors used intraperitoneal methyl methanesulfonate (40 mg per kg of animal body weight) as a positive control and 0.9% NaCl (100 μL per 100 g of animal body weight) as a negative control.Results. A single subcutaneous injection of RU-1205 to rats did not produce a significant dose-dependent increase in % tail DNA when compared with the state of the corresponding organ/tissue cell genome in negative control animals after normal saline administration at the same time points. In the negative control groups, % tail DNA in cells of various organs/tissues ranged from 1.83% to 3.82% (median values [25–75%]). On the contrary, the administration of 40 mg/kg of genotoxic methyl methanesulfonate led to an increase in damaged DNA in all studied organs and tissues when compared with negative control animals.Conclusions. The study of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a] benzimidazole dihydrochloride genotoxicity demonstrated that a single subcutaneous injection of 1, 10, or 100 mg/kg of RU-1205 to rats did not damage the cell genome of the studied organs.

The aim of the study is the investigation of the pharmacokinetic properties of the RU-1205 compound, with previously identified kappa-agonistic and analgesic effects, at a single oral administration, as well as comparison of the relationship between its pharmacokinetic and analgesic properties.Materials and methods. Pharmacokinetic parameters of RU-1205 after the oral administration at the dose of 50 mg / kg were investigated using the method of High Performance Liquid Chromatography with determination of the concentration of the compound according to the previously constructed calibration schedule. The indices of the area under the pharmacokinetic curve, clearance, half-life, residence time of the drug molecule in the body, a total (apparent) volume of distribution, as well as the indicator of absolute bioavailability, were calculated. The tissue distribution and excretion of RU-1205 were studied.Potential metabolites of RU-1205 were predicted using the PALLAS 3.00 program. The study of the analgesic activity was carried out on a model of central somatogenic pain with electricalstimulation, with the dynamics assessment of the voltage amplitude of the corresponding reaction of the "tail-flick" reflex.Results. The compound under study is rapidly adsorbed from the gastrointestinal tract, reaching a maximum concentration by the end of the first hour of the study, and is determined in plasma within 12 hours. Its half-life is 17.7 hours. The absolute oral bioavailability is 37.3%. It was found out that the compound is withdrawn within 3-4 days. The main route of excretion is extrarenal. Biotransformation of a substance probably proceeds mainly with the formation of oxidized forms of the initial molecule by reactions of the first phase of metabolic transformation. The analgesic effect is long-lasting: it starts after 15 minutes and lasts for 12 hours with flattening of the curve by the 8th hour.Conclusion. When administered orally, the test substance undergoes a long process of elimination, has the greatest tropism for the elimination organs and undergoes active biotransformation processes in the body of animals. As a result of it, active metabolic products with an analgesic activity are, possibly, formed.