Introduction. In the modern world people are exposed to the influence of adverse psychological and physical factors, escalating in intensity. The search for new pharmacodynamic effects of [1,3,5]-thiadiazine derivatives designated by significant biological activity of these compounds is an essential issue.Aim. To research adaptogenic activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives using a modified Porsolt Forced Swim Test.Materials and methods. Four substances from the group of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6Hpyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles were selected for the research. Rats were divided into a control group, 5 reference groups (amitriptyline, caffeine, thiotriazolin, thiocetam, ginseng) and 4 experimental groups according to the number of the studied original tetrahydropyrido[2,1-b][1,3,5] thiadiazine derivatives.Results. Intragastric injection of substance 2 for 5 days in the modified forced swim test (forced swimming with freight) increased work capacity and endurance of the rats by 103.42% as opposed to the initial results. The detected adaptogenic activity of this tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivative six times exceeds adaptogenic activity of ginseng and seven times that of amitriptyline. The rats in the control group were active for a bit longer time. Ginseng raised the time of activity by 17% at day 5. Caffeine essentially reduced work capacity and endurance. Amitriptyline showed adaptogenic activity at day 3 of the research (increase by 10.4%). Thiotriazolin also showed adaptogenic activity on day 3 of the research (increase by 30.17%). Thiocetam increased the time of activity by 78.55%. Substance 4 had adaptogenic activity too; it increased the time of activity in aversive conditions by 58.25%, which three times exceeds this parameter for ginseng and four times for amitriptyline.

[1,3,5]-thiadiazine derivatives exhibit interesting biological activity. Some compounds of this group have shown significant analeptic activity on the model of "thiopental anesthesia". Their effect exceeds that of caffeine benzoate. This observation prompted more detailed studies on the antidepressant activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazine.

Aim. Evaluation of the impact of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on L-DOPA effects in the tail suspension test.Materials and methods. Some tetrahydropyrido[2,1-b][1,3,5]thiadiazines exhibit a pronounced antidepressant and adaptogenic activity. We selected compounds that demonstrated the most potent antidepressant effect in the Porsolt’s forced swim test. We chose to combine two approaches in the study: estimation of the antidepressant drug impact on levodopa effects and the tail suspension test. Caffeine sodium benzoate, amitriptyline and fluoxetine were chosen as the reference compounds. Studies of the 1,3,5-thiadiazine effects on levodopa activity were undertaken to ground detailed downstream analyses of associated responses in the dopaminergic neurotransmitter system. We measured the rectal temperature in laboratory rats prior to and after tail suspension and the total active time during 5 min in the test.Results. Administration of levodopa at a dose of 150 mg/kg led to a reduction in rectal temperature and the total time of physical activity in rats in the tail suspension test. The dosage of 500 mg/kg led to a temperature increase of 0.7°C prior to and after the stress and a longer maintenance of physical activity. Rats exhibited exophthalmos and polyuria.Levodopa at a 150 mg/kg dosage in combination with caffeine sodium benzoate did not cause a significant increase in the body temperature and prolonged physical activity by 69% in the test vs. the control group. Amitriptyline in combination with levodopa at a dose of 150 mg/kg triggered a temperature increase of 1.3°C prior to and 1.85°C after tail suspension, thus leading to a prolonged physical activity. Levodopa at a dose of 150 mg/kg in combination with fluoxetine led to elevation of the body temperature by 0.6°C prior to and 0.55°C after the stress. The total active time exhibited a declining trend.The substance TD-0348 reveals an antidepressant activity. Physical active time increased by 32% in the test vs. the control group. Temperature elevation by 1.15°C prior to and 1.25°C after the stress suggests activation of the autonomic nervous system. TD-0470 in combination with levodopa (150 mg/kg) led to a rectal temperature elevation by 0.4°C prior to and 0.7°C after tail suspension. Physical activity was prolonged compared to the levodopa-treated group (150 mg/ kg). TD-0479 led to a temperature elevation by 0.85°C prior to and 0.95°C after the stress and caused polyuria. Treatment with TD-0164 did not provide sufficient data to suggest an impact on dopamine metabolism.Conclusions. The compounds TD-0348, TD-0470 and TD-0479 affect physiological processes in experimental rats in response to treatment with L-DOPA at a dose of 150 mg/kg, which suggests the autonomic nervous system (ANS) activation. TD-0470 exhibits antidepressant properties. Treatment with TD-0164 does not provide sufficient data to evaluate its dopamine-related effects.

In present medical practice adaptogens and antihypoxants are a promising, but still insufficiently studied group of medicines. The largest evidence base among plant adaptogens was developed for ginseng, aralia, eleutherococcus, lemongrass, rhodiola, leuzea, sterculia. Antihypoxants, like trimetazidine, meldonium, succinic and -aminobutyric acid medications are included in the clinical guidelines. They have the most pronounced antihypoxic effects in a variety of diseases and pathological conditions, accompanied by impaired energy metabolism in the tissues. But their effect is not always high due to the variety of etiological factors causing hypoxia. Tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives characterized by various pharmacodynamic effects with low toxicity which opens up prospects for a detailed further study. In animal experiments, the most pronounced adaptogenic and antidepressant effects is exerted by compounds TD-0348 and TD-0479, superior in strength to the antihypoxants used in modern clinical practice, the classic plant adaptogen ginseng.

A series of 1,3,5-thiadiazine derivatives exhibited high antidepressant and adaptogenical activity. We decided to unite two techniques for further research: evaluation of the impact of compounds with antidepressant activity on levodopa effects and the test of suspension by the tail. For comparison we chose: caffeine-sodium benzoate, amitriptyline and fluoxetine. Evaluation of the impact of 1,3,5thiadiazine derivatives on levodopa effects was chosen for more detailed analysis effects of studied substances on dopamine metabolism.