Chemical Papers

, Volume 73, Issue 2, pp 509–515 | Cite as

Effect on AMPA receptors and lipophilicity of substituted pyridoindoles as potential neuroprotectors

  • Svetlana Blokhina
  • Marina Ol’khovich
  • Angelica SharapovaEmail author
Original Paper


The effect of the chemical nature of substituents (–H, –CH3–, –OCH3, –F and –Cl) introduced into the tricyclic fragment of hydrogenated pyrido[4,3-b]indoles on the compounds ability to positively modulate the activity of ionotropic glutamate AMPA receptors have been studied. The unsubstituted derivative, compounds with a methyl group and a fluorine atom were found to have the highest bioactivity in this test. The partition coefficients of the synthesized derivatives in the system 1-octanol/buffer pH 7.4 in the temperature range of 293.15–313.15 K have been measured. It has been found that as the lipophilicity of the compounds studied increases, the maximum biological activity is achieved at a higher concentration of the administered substance. The thermodynamic transfer functions of the studied substances from aqueous medium to organic phase have been calculated.


Derivatives of Dimebon Bioactivity 1-Octanol/buffer pH 7.4 system Partition coefficient Transfer thermodynamics 



This work was supported by the grant of RFBR no. 18-43-370016.

Compliance with ethical standards

Conflict of interest

The authors report that there are no conflicts of interest in this article.

Supplementary material

11696_2018_595_MOESM1_ESM.xls (48 kb)
Supplementary material 1 (XLS 48 kb)


  1. Albert A (2012) Selective toxicity: the physico-chemical basis of therapy. Springer, New YorkGoogle Scholar
  2. Arnott JA, Planey SL (2012) The influence of lipophilicity in drug discovery and design. Curr Top Med Chem 13:1317–1326. Google Scholar
  3. Blokhina S, Sharapova A, Ol’khovich M et al (2018) New derivatives of hydrogenated pyrido[4,3-b]indoles as potential neuroprotectors: synthesis, biological testing and solubility in pharmaceutically relevant solvents. Saudi Pharm J. Google Scholar
  4. Chang RC-C (2011) Advanced understanding of neurodegenerative diseases. InTech, RijekaCrossRefGoogle Scholar
  5. Doody RS, Gavrilova SI, Sano M et al (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet 372:207–215. CrossRefGoogle Scholar
  6. Eckert SH, Eckmann J, Renner K et al (2012) Dimebon ameliorates amyloid-β induced impairments of mitochondrial form and function. J Alzheimer Dis 31:21–32. CrossRefGoogle Scholar
  7. Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1:55–68. CrossRefGoogle Scholar
  8. Hansch C (1971) Quantitative structure–activity relationship in drug design. In: Ariens EJ (ed) Drug design. Academic Press, New York, pp 271–342Google Scholar
  9. Hung DT, Protter AA, Jain RP et al (2015) Tetracyclic compounds, Patent US8999978 B2Google Scholar
  10. Kaneda M, Nakamura H, Akaike N (1988) Mechanical and enzymatic isolation of mammalian CNS neurons. Neurosci Res 5:299–315. CrossRefGoogle Scholar
  11. Kerns E, Li D (2008) Drug like properties: concepts, structure design and methods. Academic Press, New YorkGoogle Scholar
  12. Khritankova IV, Kukharskiy MS, Lytkina OA et al (2012) Dimebon activates autophagosome components in human neuroblastoma SH-SY5Y cells. Dokl Biochem Biophys 446:251–253. CrossRefGoogle Scholar
  13. Lynch G (2006) Glutamate-based therapeutic approaches: ampakine. Curr Opin Pharmacol 6:82–88. CrossRefGoogle Scholar
  14. Molleman A (2003) Patch clamping: an introductory guide to patch clamp electrophysiology. Wiley, ChichesterGoogle Scholar
  15. Shaffer CL, Hurst RS, Osgood SM et al (2013) Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574. J Pharmacol Exp Ther 347:212–224. CrossRefGoogle Scholar
  16. Steele JW, Gandy S (2013) Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagic Punctum 9:617–618. Google Scholar
  17. Thomas G (2000) Medicinal chemistry an introduction. Wiley, West SussexGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  • Svetlana Blokhina
    • 1
  • Marina Ol’khovich
    • 1
  • Angelica Sharapova
    • 1
    Email author
  1. 1.Institute of Solution ChemistryRussian Academy of SciencesIvanovoRussia

Personalised recommendations