Neurology, Neuropsychiatry, Psychosomatics

Advanced search

Chemoreactome analysis of ethylmethylhydroxypyridine succinate

Full Text:


Ethylmethylhydroxypyridine succinate (EMHPS) is used in the therapy of ischemic stroke. A more complete understanding of the conditions that can affect the clinical efficacy of EMHPS needs the most complete information about its molecular mechanisms of action.

Objective: to comparatively analyze the properties of EMHPS using the newest area of postgenomic pharmacology – chemoreactome simulation. Succinic acid and citicoline were used as the molecules of comparison (control molecules).

Material and methods. Chemoreactome analysis was employed to assess the biological activity of a test molecule (simulation of the affinity profile of the examined molecular structure for various proteome proteins). A new mathematical method based on the combinatorial theory of solvability was devised for chemoinformational analysis.

Results and discussion. Chemoreactome simulation has shown that EMHPS may be an agonist of acetylcholine and GABA receptors, as well as that of cannabinoid receptor type 2. The anti-inflammatory effect of an EMHPS molecule may be due to the inhibition of synthesis of proinflammatory prostaglandins. Its higher safety (a weaker effect on serotonin and opioid receptors and lower interaction with Erg channels and the enzymes monoamine oxidase and cytochrome CYP1A1) distinguish EMHPS from the molecules of comparison (citicolne and succinic acid). The predicted properties of the molecule of EMHPS make a substantial contribution to its neuroprotective effect.

Conclusion. The results of chemoreactome analysis could reveal not only quite unexpected mechanisms of action of EMHPS, but also its mechanisms of synergic action with pyridoxine and magnesium. Owing to a combination of EMHPS with pyridoxine and magnesium, there is an increase in the antioxidant, anticonvulsant, stress- and neuroprotective, nootropic, and anxiolytic effects of EMHPS via activation of pyridoxine-dependent and magnesium-dependent proteins. The combination of EMHPS with pyridoxine and magnesium also contributes to the potentiation of hemodynamic, antiplatelet, antiaggregant, and anticoagulant actions, activates homocysteine neutralization and anti-inflammatory protection, and decreases the risk of proarrhythmic effects.

About the Authors

O. A. Gromova
Ivanovo State Medical Academy, Ministry of Health of Russia, Ivanovo, Russia 8, Sheremetevsky Passage, Ivanovo 153000
Russian Federation

I. Yu. Torshin
Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia 9, Institutskiy Lane, Dolgoprudnyi, Moscow Region 141700
Russian Federation

L. E. Fedotova
Ivanovo State Medical Academy, Ministry of Health of Russia, Ivanovo, Russia 8, Sheremetevsky Passage, Ivanovo 153000
Russian Federation

A. N. Gromov
Federal Research Center «Information Science and Management», Russian Academy of Sciences, Moscow, Russia 44, Vavilov St., Moscow 119333
Russian Federation


1. Об утверждении перечней жизненно необходимых и важнейших лекарственных препаратов для медицинского применения на 2016 год. Распоряжение от 26 декабря 2015 года №2724-р. [On approval of the list of vital and essential medicinal products for medical use by 2016. The order from December 26, 2015 No. 2724-p].

2. Rumyantseva SA, Fedin AI, Sokhova ON. Antioxidant Treatment of Ischemic Brain Lesions. Neuroscience and Behavioral Physiology. 2012;42(8):842–5. doi:10.1007/s11055-012-9646- 3.

3. Torshin I, Gromova O. Magnesium and pyridoxine: fundamental studies and clinical practice. NovaScience; 2009. 250 p.

4. Парфенов ВА. Постинсультная депрессия: распространенность, патогенез, диагностика и лечение. Неврология, нейропсихиатрия, психосоматика. 2012;4(4):84-8. [Parfenov VA. Poststroke depression: prevalence, pathogenesis, diagnosis, and treatment. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2012;4(4):84-8. (In Russ.)]. doi: 10.14412/ 2074-2711-2012-428

5. Edalati-Fard F, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Farshbaf-Khalili A. Relationship of zinc and magnesium serum levels with postpartum depression in Tabriz- Iran. Glob J Health Sci. 2016 Mar 1; 8(11):55886. doi:10.5539/gjhs.v8n11p120.

6. Косенко ВГ, Карагезян ЕА, Лунева ЛВ, Смоленко ЛФ. Применение мексидола в психиатрической практике. Журнал неврологии и психиатрии им. С. С. Корсакова. 2006;(6):38-41. [Kosenko VG, Karagezyan EA, Luneva LV, Smolenko LF. The use of Mexidol in psychiatric practice. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2006;(6):38-41. (In Russ.)].

7. Volchegorskii IA, Miroshnichenko IY, Rassokhina LM, et al. Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives. Bull Exp Biol Med. 2015 Apr;158(6):756-61. doi:10.1007/s10517-015-2855-3. Epub 2015 Apr 21.

8. Torshin IYu. Bioinformatics in the postgenomic era: physiology and medicine. New York: NovaBiomedicalBooks; 2007.

9. Рудаков КВ, Торшин ИЮ. Анализ информативности мотивов на основе критерия разрешимости в задаче распознавания вторичной структуры белка. Информатика и еe применение. 2011;5(4):40-50. [Rudakov KV, Torshin IYu. Analysis of information content of motifs based on the criterion of solvability in the problem of protein secondary structure recognition. Informatika i ee primeneniе. 2011;5(4): 40-50. (In Russ.)].

10. Журавлeв ЮИ, Рудаков КВ, Торшин ИЮ. Алгебраические критерии локальной разрешимости и регулярности как инструмент исследования морфологии аминокислотных последовательностей. Труды МФТИ. 2011;3(4):67-76. [Zhuravlev YuI, Rudakov KV, Torshin IYu. Algebraic criteria for local solvability and regularity as a tool to investigate the morphology of amino acid sequences. Trudy MFTI. 2011;3(4):67-76. (In Russ.)].

11. Torshin IYu, Rudakov KV. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognition and Image Analysis. 2014;24(1):11-23.

12. Torshin IYu, Rudakov KV. On the application of the combinatorial theory of solvability to the analysis of chemographs: Part 2. Local completeness of invariants of chemographs in view of the combinatorial theory of solvability. Pattern Recognition and Image Analysis. 2014; 24(2):196-208.

13. Журавлев ЮИ. Теоретико-множественные методы в алгебре логики. Проблемы кибернетики. 1962;8(1):25-45. [Zhuravlev YuI. Set-theoretic methods in the algebra of logic. Problemy kibernetiki. 1962;8(1):25-45. (In Russ.)].

14. Журавлев ЮИ. Об алгебраическом подходе к решению задач распознавания или классификации. Проблемы кибернетики. Москва: Наука; 1978. С. 5-68. [Zhuravlev YuI. Ob algebraicheskom podkhode k resheniyu zadach raspoznavaniya ili klassifikatsii [About algebraic approach to solving the problems of recognition or classification]. Problemy kibernetiki. Moscow: Nauka; 1978. P. 5-68.]

15. Torshin IYu. Bioinformatics in the postgenomic era: sensing the change from molecular genetics to personalized medicine. New York: NovaBiomedicalBooks; 2009

16. Торшин ИЮ, Громова ОА. Экспертный анализ данных в молекулярной фармакологии. Москва: Издательство МЦНМО; 2012. 768 с. [Torshin IYu, Gromova OA. Ekspertnyi analiz dannykh v molekulyarnoi farmakologii [Expert data analysis in molecular pharmacology]. Moscow: Izdatel'stvo MTsNMO; 2012. 768 p.]

17. Bolton E, Wang Y, Thiessen PA, Bryant SH. PubChem: integrated platform of small molecules and biological activities. chapter 12. In: Annual reports in computational chemistry, volume 4. Washington, DC: American Chemical Society; 2008.

18. Wishart DS, Tzur D, Knox C, et al. HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007 Jan;35(Database issue):D521-6.

19. Olianas MC, Dedoni S, Onali P. Protection from interferon-beta-induced neuronal apoptosis through stimulation of muscarinic acetylcholine receptors coupled to ERK1/2 activation. Br J Pharmacol. 2016 Oct;173(19):2910- 28. doi:10.1111/bph.13570. Epub 2016 Aug 26.

20. Lin NH, Gunn DE, Ryther KB, et al. Structure-activity studies on 2-methyl-3-(2(S)- pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognitionenhancing properties. J Med Chem. 1997 Jan 31;40(3):385-90.

21. Nakamura M, Jang IS. Muscarinic M4 receptors regulate GABAergic transmission in rat tuberomammillary nucleus neurons. Neuropharmacology. 2012 Nov;63(6):936-44. doi:10.1016/j.neuropharm.2012.07.007. Epub 2012 Jul 22.

22. Vandevrede L, Tavassoli E, Luo J, et al. Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABA(A) receptor potentiation. Br J Pharmacol. 2014 Jan;171(2):389-402. doi:10.1111/bph.12454.

23. Avolio E, Mahata SK, Mantuano E, et al. Antihypertensive and neuroprotective effects of catestatin in spontaneously hypertensive rats: interaction with GABAergic transmission in amygdala and brainstem. Neuroscience. 2014 Jun 13;270:48-57. doi:10.1016/j.neuroscience. 2014.04.001. Epub 2014 Apr 13.

24. Beltramo M, Bernardini N, Bertorelli R, et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006 Mar;23(6):1530-8.

25. Leichsenring A, Andriske M, Backer I, et al. Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jun;379(6):627-36. doi:10.1007/s00210-008-0386-4. Epub 2009 Jan 18.

26. Kim K, Moore DH, Makriyannis A, Abood ME. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol. 2006;542 (1-3):100-5 Epub 2006 May.

27. Shoemaker JL, Seely KA, Reed RL, et al. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem. 2007;101(1): 87-98 Epub 2007 Jan.

28. Montecucco F, Burger F, Mach F, Steffens S. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294(3):H1145-55

29. Ghosh S, Preet A, Groopman JE, Ganju RK. Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. Mol Immunol. 2006; 43(14):2169-79

30. Palazuelos J, Aguado T, Egia A, et al. Nonpsychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 2006;20(13):2405-7

31. Voronina TA. Mexidol: the spectrum of pharmacological effects. Zh nevrol psikhiatr im SS Korsakova. 2012;112(12):86-90.

32. Young W. Spinal cord regeneration. Cell Transplant. 2014;23(4-5):573-611

33. Gaikwad AB, Viswanad B, Ramarao P. PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance. Pharmacol Res. 2007;55(5):400-7

34. Braga RC, Alves VM, Silva MF, et al. Tuning HERG out: antitarget QSAR models for drug development. Curr Top Med Chem. 2014; 14(11):1399-1415.

35. Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006;440(7083):463-9.

36. Schildkraut JJ, Herzog JM, Orsulak PJ, et al. Reduced platelet monoamine oxidase activity in a subgroup of schizophrenic patients. Am J Psychiatry. 1976;133(4):438-40.

37. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63(11):1209-16.

For citation:

Gromova O.A., Torshin I.Y., Fedotova L.E., Gromov A.N. Chemoreactome analysis of ethylmethylhydroxypyridine succinate. Neurology, Neuropsychiatry, Psychosomatics. 2016;8(3):53-60. (In Russ.)

Views: 260

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)