Background. Studies conducted in the past two decades in different countries have shown that depression is common in the practice of therapist. The prevalence of depressive disorders depends on the country and residence region, but the average estimates suggest that depression occurs in 10-20% of patients of primary health care [1]. It has been shown that the risk of coronary heart disease and stroke is increased in patients with depression [2, 3].

[1,3,5]-Thiadiazine derivatives are characterized by significant biological activities [4-8]. Some compounds of this group of substances exhibited significant analeptic activity on the model "thiopental anesthesia". Their effect is exceeding that of the caffeine benzoate by several times [9]. This observation prompted more detailed studies of the antidepressant activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazines.

Objective. Assessment of antidepressant activity tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on the model of "behavioral despair" with the forced swimming by Porsolt.

Materials and methods. Four substances were selected from the group of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles (1-4), synthesized with by an uncatalyzed Mannich reaction [4, 8]. These substances showed the most effective  analeptic activity in previous studies on a model of "thiopental anesthesia".

Pharmacological studies were conducted on 36 adult albino rats weighing 230-270 g in autumn-winter period in an approved pharmaceutical laboratory SI "Lugansk State Medical University". The rats were divided into control group, the reference group (amitriptillin 5 mg / kg) and 4 experimental groups according to the number of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives in a similar dosage.

Stress state has been induced by the forced swimming, according to the generally accepted method [10]. The effect of the studied  tetrahydropyrido [2,1-b] [1,3,5] thiadiazines was estimated by the number of attempts to get rid of the situation and the duration of the animal activity.

Results and discussion. In the test of "behavioral despair", animals in the control group made a series of attempts of deliverance and then a stage of immobilization came. In that control group, the duration of activity was 1 minute 13 seconds. The reference group receiving the tricyclic antidepressant amitriptyline, attempted to get rid of the situation for a period exceeding 2.22 times the duration in the control group. Activity time exceeded by 3.88 times that observed in the control group. Laboratory rats receiving substances 2 and 3 shown an ability to increase the number of attempts to get rid of the situation and a longer time of activity. The number of attempts to get rid of the situation in these groups exceeded the number in the control group by 132.6% and 125.6%, respectively. Activity time for rats in the experimental group 2 exceeded the activity time of the control group by 117.1%.

        Conclusions. In the model of test "behavioral despair" with the forced swimming in albino rats,  the antidepressant activity of some compounds 3-R-8-Ar-6-oxo-3,4,7,8-tetrahydro-2H, 6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles was studied and compared to the activity of amitriptyline. For substance 2 (Ar = 4-MeOC₆H₄, R = cyclohexyl) and 3 (Ar = 3,4-(MeO)₂C₆H₃, R = 2-Me-3-Cl-C₆H₃) the antidepressive effect considerably exceeded that of the reference drug. Further studies with analogs of such fused compounds are currently in progress.

References

1. Krasnov V.N. Psihiatricheskie rasstroistva v obschemedicinskoi praktike [Psychiatric disorders in general medical practice] RMJ 2002;25:1187 – 1191 (in Russian)
2. Ariyo A.A., Haan M., Tangen C.M. et al. Depressive symptoms and risk of coronary heart disease and mortality in elderly Americans/ Circulation 2000;102:1773.
3. Larson S.L., Owens P.L., Ford D., Eaton W. Depressive disorder, dysthymia, and risk of stroke. Thirteen-year follow-up from the Baltimore Epidemiologic Catchment Area Study. Stroke 2001;9:1979.
4. J.C. Bermello, R. P. Piñeiro, L.M. Fidalgo, H.R. Cabrera, M.S. Navarro. Thiadiazine Derivatives as Antiprotozoal New Drugs // The Open Medicinal Chemistry Journal, 2011, № 5, рр. 51-60.
5. В.В. Доценко, К.А. Фролов, С.Г. Кривоколыско. Синтез частично гидрированных 1,3,5-тиадиазинов по реакции Манниха // Химия гетероциклических соединений 2015, Т. 51, № 2, с. 109–127. [Chem. Heterocycl. Compd. 2015, 51(2), 109–127].
6. N. Shobana, P. Farid. 1,3,5-Oxadiazines and 1,3,5-Thiadiazines // In  Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. (Eds.); Elsevier: Oxford, 2008, vol. 9, pp. 457-521.
7. H. Rodríguez, M. Suárez, F. Albericio. Thiadiazines, N,N-Heterocycles of Biological Relevance // Molecules 2012, 17, pp. 7612-7628; doi:10.3390/molecules17077612.
8. Osolodkin Dmitry I. Inhibitors of Tick-Borne Flavivirus Reproduction from Structure-Based Virtual Screening / Dmitry I. Osolodkin, Liubov I. Kozlovskaya, Evgenia V. Dueva, Victor V. Dotsenko, Yulia V. Rogova, Konstantin A. Frolov, Sergey G. Krivokolysko, Ekaterina G. Romanova, Alexey S. Morozov, Galina G. Karganova, Vladimir A. Palyulin,Vladimir M. Pentkovski, Nikolay S. Zefirov // ACS Med. Chem. Lett. – 2013. – 4. –РР. 869−874. http://pubs.acs.org/doi/abs/10.1021/ml400226s
9. Bibik E. Yu., Yaroshevskaya O.G., Mischuk A.A., Frolov K.A., Docenko V.V., Krivokolisko S.G. /Izuchenie analepticheskoi aktivnosti proizvodnih tetragidropirido[2,1-b][1,3,5]tiadiazina // Tezisi nauchno_prakticheskoi konferencii «Himicheskie problemi sovremennosti» [Study of the analeptic activity of tetrahydropyrido [2,1-3] [1,3,5] thiadiazine derivatives // Abstracts of the scientific and practical conference "Chemical problems of the present"], Donetsk, 2016. – p. 104-106 (in Russian)
10. Habriev G.U. Rukovodstvo po eksperimentalnomu doklinicheskomu izucheniyu novih farmakologicheskih veschestv [Manual on experimental preclinical study of new pharmacological substances], Medicine, Moscow. – 2005. – p. 832 (in Russian)