Neurochemical aspects of the cardiotropic compound ALM-802S pharmacological activity

Introduction. The compound ALM-802S, which has a pronounced cardiotropic effect, has been identified among the alkoxyphenyltriazoalkanes. The structure of this substance includes 2 pharmacophore components of the cardioprotective agent trimetazidine, which can potentially cause extrapyramidal disorders. The ALM-802S compound, in addition to its cardiotropic activity, has anxiolytic and analgesic effects. It is possible that the ALM-802S compound, acting on the central and peripheral serotonergic and dopaminergic mediator systems, may, like trimetazidine, cause central side effects.

The study aim. It was to evaluate the effect of the ALM-802S compound on the content of biogenic catecholamines, indolamines and their metabolites in blood plasma and separate brain structures in rats.

Materials and methods. The experiments were carried out on white male rats weighing 180–200 g. The test substance was administered at a dose of 5 mg/ kg i./p. 60 minutes before decapitation. The content of indolamines and catecholamines in blood plasma and brain structures was determined using HPLC/ED.

Results. Analysis of the obtained data showed that the compound ALM-802S with a single systemic administration does not affect the content of indolamines in blood plasma and brain structures of rats. Measurements of the catecholamine content showed that the ALM-802S compound significantly reduced the concentration of DOPA and HCV in blood plasma, the content of A, HA, DA, DOPA and the ratio of metabolites remained virtually unchanged. Of all the studied brain structures, only in the hypocampus there was a decrease in the GVK/DA ratio, which characterizes the DA decay rate. No changes were found in the rest of the brain structure.

Conclusion. Using neurochemical analysis, information was obtained on the absence of a pronounced effect of ALM-802S on the functional activity of the central dopaminergic and serotonergic systems, which minimizes the possibility of extrapyramidal disorders and the development of drug dependence when using ALM-802S in therapeutic doses.

1. Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: a clinical review. Eur Heart J. 2014 Jun 1;35(21):1365-72. doi: 10.1093/eurheartj/eht462.

2. Zhao Q, Sun X, Zhang Y, et al. Network analysis of anxiety and depressive symptoms among patients with heart failure. BMC Psychiatry. 2024 Nov 14;24(1):803. doi: 10.1186/s12888-024-06259-0.

3. Liu M, Wei W, Stone CR, et al. Beneficial effects of trimetazidine on expression of serotonin and serotonin transporter in rats with myocardial infarction and depression. Neuropsychiatr Dis Treat. 2018 Mar 16;14:787-797. doi: 10.2147/NDT.S157441.

4. Kolik LG, Nadorova AV, Stolyaruk VN, et al. Anxiolytic properties of trimetazidine in experimental models of increased anxiety. Bull Exp Biol Med. 2016;162(11):593-597. (In Russ.). doi: 10.1007/s10517-017-3677-2. EDN: XGVGAX

5. Barchukov VV. Poisk kardiotropnyh sredstv v ryadu linejnyh i ciklicheskih alkoksifenilazaalkanov. [dissertation] Moscow; 2024. (In Russ.)]. Доступно по: https://www.academpharm.ru/images/upload/ru/1673/Barchukov_DISSERTACIYA.pdf. Ссылка активна на 01.07.2025.

6. Erbaş O, Akseki HS, Eliküçük B, Taşkıran D. Antipsychotic-like effect of trimetazidine in a rodent model. ScientificWorldJournal. 2013 Oct 22;2013:686304. doi: 10.1155/2013/686304.

7. Bortolasci CC, Kidnapillai S, Spolding B, et al. Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression. Bipolar Disord. 2023 Dec;25(8):661-670. doi: 10.1111/bdi.13319.

8. Khanra S, Reddy P, Giménez-Palomo A, et al. Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine. Mol Psychiatry. 2023 Aug;28(8):3231-3242. doi: 10.1038/s41380-023-02134-8.

9. Martí Massó JF, Martí I, Carrera N, et al. Trimetazidine induces parkinsonism, gait disorders and tremor. Therapie. 2005 Jul-Aug;60(4):419-22. doi: 10.2515/therapie:2005061.

10. Bondon-Guitton E, Perez-Lloret S, Bagheri H, et al. Drug-induced parkinsonism: a review of 17 years' experience in a regional pharmacovigilance center in France. Mov Disord. 2011 Oct;26(12):2226-31. doi: 10.1002/mds.23828.

11. Masmoudi K, Masson H, Gras V, Andréjak M. Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases. Fundam Clin Pharmacol. 2012 Apr;26(2):198-203. doi: 10.1111/j.1472-8206.2011.01008.x.

12. Pintér D, Kovács M, Harmat M, et al. Trimetazidine and parkinsonism: A prospective study. Parkinsonism Relat Disord. 2019 May;62:117-121. doi: 10.1016/j.parkreldis.2019.01.005.

13. Kryzhanovskii SA, Likhosherstov AM, Tsorin IB, et al. Screening of the сompounds having cardiotropic activity among the α, ω-diarilmetil derivatives of bis-(ω-aminoalkyl)amines. Pharmacokinetics and Pharmacodynamics. 2016;(2):10-13 (In Russ.).

14. Barchukov VV, Zinchenko VP, Tsorin IB, et al. Features of the compound ALM-802 antiarrhythmic action. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharma-codynamics. 2023;(3):56-67. (In Russ.). doi: 10.37489/2587-7836-2023-3-56-67.

15. Barchukov VV, Stolyaruk VN, Tsorin IB, et al. Study of the antiarrhythmic activity of linear alkoxyphenylazalkanes in the model of reperfusion arrythmias in rats. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2023;(2):20-28. (In Russ.). doi: 10.37489/2587-7836-2023-2-20-28.

16. Barchukov VV, Tsorin IB, Likhosherstov AM, et al. A comparative study of the anti-ischemic activity of trimetazidine and the compound ALM-802 under conditions of endothelial dysfunction. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2019;(2):23-27. (In Russ.). doi: 10.24411/2588-0519-2019-10042.

17. Tsorin IB, Barchukov VV, Vititnova MB, et al Cardioprotective effects of compound ALM-802 on subendocardial ischemia models. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2021;(1):18-22. (In Russ.). doi: 10.37489/2587-7836-2021-1-18-22.

18. Barchukov VV, Tsorin IB, Vititnova MB, et al. Choice of tactics for experimental therapy of chronic heart failure with ALM-802 compound. Bull Exp Biol Med. 2020;170(12):764-767. (In Russ.). doi: 10.47056/0365-9615-2020-170-12-764-767. EDN: VHLKUY

19. Kolik LG, Nadorova AV, Tsorin IB, et al. Experimental evaluation of the anxiolytic and analgesic properties of a new derivative of linear methoxyphenyltriazaalkanes with cardiotropic activity. Bull Exp Biol Med. 2020;170(12):752-758. (In Russ.). doi: 10.47056/0365-9615-2020-170-12-752-758.

20. Zhang LJ, Liu MY, Rastogi R, Ding JN. Psychocardiological disorder and brain serotonin after comorbid myocardial infarction and depression: an experimental study. Neurol Res. 2018 Jun;40(6):516-523. doi: 10.1080/01616412.2018.1455460.

21. Kim S, Yu YM, Kwon J, et al. Trimetazidine Use and the Risk of Parkinsonism: A Nationwide Population-Based Study. Int J Environ Res Public Health. 2020 Oct 4;17(19):7256. doi: 10.3390/ijerph17197256.

22. Dy AMB, Limjoco LLG, Jamora RDG. Trimetazidine-Induced Parkinsonism: A Systematic Review. Front Neurol. 2020 Feb 25;11:44. doi: 10.3389/fneur.2020.00044.

23. Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease. Eur J Neurol. 2013 Jan;20(1):5-15. doi: 10.1111/j.1468-1331.2012.03866.x.

24. Masmoudi K, Gras-Champel V, Douadi Y, et al. La trimetazidine-- nouvelle etiologie de troubles extrapyramidaux: un cas de syndrome parkinsonien avec akathisie [Trimetazidine-a new aetiology for extrapyramidal disorders: A case of parkinsonism and akathisia]. Therapie. 2005 NovDec;60(6):603-5. French. doi: 10.2515/therapie:2005090.

25. Kolic LG, Nadorova AV, Narkevich VB, Kudrin VS. The Derivative of aminoadamantane hemantane alleviates morphin-induced hyperlocomotion via modulation of activity of the dopaminergic and serotonergic systems. Neurochemistry. 2020;37(1):54-63. (In Russ.). doi: 10.31857/S1027813320010136.

26. Engalycheva GN, Syubaev RD, Goryachev DV. Safety Pharmacology Studies of Medicinal Products: Evaluation of Results. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2017;7(2):92-97. (In Russ.). doi: 10.30895/1991-2919-2017-7-2-92-97.