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The aim of the study was to assess the probability of developing withdrawal syndrome caused by discontinuation of 5-day administration of thiowurtzine with naloxone challenge test in the experiment.Materials and methods. The test sample of the analgesic “Thiowurtzine, capsule 120 mg” served as the study object. The active pharmaceutical ingredient is an organic, low molecular weight compound 4-(3,4-dibromothiophene carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5,5,0,03,11,05,9]dodecane that was first synthesized according to computer modeling results at the IPCET SB RAS (Biysk).The likelihood of developing physical dependence was explored by per os administration of thiowurtzine and the reference drug tramadol twice a day for 5 days as follows: 1) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg; 2) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 3) at 9 a.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 4) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg; 5) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – naloxone 10 mg / kg subcutaneously.In all the groups, the intensity of the withdrawal syndrome was studied by specific features in outbred male CD1 mice. During one hour following the naloxone injection, health of mice was assessed according to dominant abstinence components and recessive traits of mild withdrawal syndrome. Two hours after the naloxone injection, the number of mice with negative body weight gain was determined. 24 hours after discontinuation of test compound administration, the open-field test was used to determine the impact on animal behavioral patterns (horizontal and vertical motor and exploratory activity, emotionality and its vegetative manifestations). The hot plate test was carried out to measure the analgesic activity (55˚). The criterion of the withdrawal syndrome severity was a decrease in the number of jumping reactions, changes in the general condition of the animals, stimulation of motor activity, manifestations of hyperalgesia, and a decrease in body weight.Results. No dominant abstinence components and recessive signs of withdrawal syndrome were detected in animals from the thiowurtzine groups. The data obtained in the study (orientation and exploratory behavior, motor activity, emotionality and its vegetative manifestations, grooming, etc.) allow to conclude that thiowurtzine causes no physical dependence in animals after discontinuation of its 5-day administration with naloxone challenge test, as opposed to the reference drug naloxone. A positive disinhibition effect of this analgesic was revealed due to the activated orientation and exploratory behavior (stress caused by the new environment) in the conditions of the open-field test. The animals showed no manifestations of hyperalgesia in the hot plate test. The animals treated with thiowurtzine did not demonstrate any changes in the body weight.Conclusion. The obtained results prove that thiowurtzine is a non-narcotic analgesic. It evokes no side effects typical of opioid analgesics (tramadol), including development of physical dependence and withdrawal syndrome following naloxone challenge test. Previous in vivo and in silico studies (docking, molecular modeling, molecular dynamics simulation) on the multi-target mechanism of thiowurtzine explain the absence of its morphine-like effect by the fact that the major targets of the analgesic are TRPA1 receptors and voltage-gated Ca 2+ channels. With a high degree of probability, the conclusions made herein predict no drug abuse development when thiowurtzine is used in the clinical setting. Absence of ulcerotoxicity found earlier will enable to administer thiowurtzine in long-term cycles for chronic pain syndrome.

The aim of this study was to assess the analgesic action of thiowurtzine in somatogenic nociception models by activation of TRPA1 and TRPV1 ion channels. Materials and methods. The object of the study is the compound 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5.5.0. 03,11 .0 5,9 ]dodecane ( t hiowurtzine). The analgesic activity of thiowurtzine was studied under the conditions of a chemogenic activation model of TRPA1 channels (by the formalin test), and by a selective test with an agonist of TRPV1 channels (the capsaicin test). The compound was administered once per os in a dose range of 50–200 mg/kg (water-tween solvent) an hour before the experimental manipulations. The reference drugs were diclofenac sodium in a preventive single per os dose of 10 mg/kg in 1% starch gel in a volume of 0.2 ml/mouse, and ketorolac in a dose of 6 mg/kg in the same solvent, volume and route of administration. Results. T hiowurtzine, when administered in per os doses of 100 and 200 mg/kg, was found to effectively block nociceptive reactions caused by activation of TRPA1 and TRPV1 ion channels. At the same time, the analgesic activity of t hiowurtzine turned out to be comparable and/(or) superior to the ketorolac and diclofenac action, depending on the model situation. In addition, it was found that t hiowurtzine (200 mg/kg per os ) corresponds to diclofenac sodium (10 mg/kg per os ) and is superior to ketorolac (6 mg/kg per os ) in terms of anti-inflammatory severity in the formalin test. Conclusion . The biphasicity of behavioral reactions in the prognostic formalin test do not allow for an unambiguous conclusion about the direction of the action mechanism of thiowurtzine, which confirms the polymodality hypothesis. The data obtained in the two models of somatogenic nociception do not exclude the fact that the modulation of the TRPA1 and TRPV1 activity is one of the mechanisms of the thiowurtzine analgesic action. By the key analgesic characteristics found herein, thiowurtzine proves to be a unique compound with a high therapeutic and innovation potential.