Novel Positive Allosteric Modulators of AMPA Receptors Based on 3,7-Diazabicyclo[3.3.1]nonane Scaffold

  • Mstislav I. Lavrov
  • Dmitry S. Karlov
  • Tatiana A. Voronina
  • Vladimir V. Grigoriev
  • Aleksey A. Ustyugov
  • Sergey O. BachurinEmail author
  • Vladimir A. PalyulinEmail author


A series of new positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors based on 3,7-diazabicyclo[3.3.1]nonane scaffold have been designed, synthesized, and analyzed. In electrophysiological patch clamp studies, several compounds have demonstrated a sub-nanomolar potency. Compound 4 in in vivo tests showed anti-amnestic properties in the scopolamine-induced model of amnesia in the step-through passive avoidance or maximal electroshock experiments in rats at 0.01 mg/kg showing a significant “dose-response” advantage over memantine. Based on the analysis of the flexible docking results of PAMs, the cyclothiazide-like mechanism of binding mode was suggested as the major site for the interaction with AMPA receptors.


3,7-Diazabicyclo[3.3.1]nonanes AMPA receptor Positive allosteric modulators (PAMs) Patch clamp Scopolamine Step-through passive avoidance Anti-amnestic compounds 



positive allosteric modulators

AMPA receptors

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors


step-through passive avoidance


maximal electroshock



The animal facilities and equipment of the “Centre for Collective Use of IPAC RAS” were used.

Funding Information

Molecular modeling and docking studies were supported by Russian Science Foundation grant no. 17-15-01455. Biological part of the study was supported by the IPAC RAS State Targets Project no. 0090-2019-0005.

Compliance with Ethical Standards

All experiments were approved by the Institutional Animal Review Board and were conducted in accordance with the Russian law “On Establishing Rules of Good Laboratory Practice” (23.09.2010, no. 708n).

Supplementary material

12035_2019_1768_MOESM1_ESM.docx (139 kb)
ESM 1 (DOCX 138 kb)


  1. 1.
    Francotte P, de Tullio P, Fraikin P, Counerotte S, Goffin E, Pirotte B (2006) In search of novel AMPA potentiators. Recent Pat CNS Drug Discov 1(3):239–246CrossRefGoogle Scholar
  2. 2.
    Greger IH, Esteban JA (2007) AMPA receptor biogenesis and trafficking. Curr Opin Neurobiol 17(3):289–297. CrossRefGoogle Scholar
  3. 3.
    Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H et al (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496. CrossRefGoogle Scholar
  4. 4.
    Palmer CL, Cotton L, Henley JM (2005) The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev 57(2):253–277. CrossRefGoogle Scholar
  5. 5.
    O’Neill MJ, Dix S (2007) AMPA receptor potentiators as cognitive enhancers. IDrugs 10(3):185–192Google Scholar
  6. 6.
    Pirotte B, Francotte P, Goffin E, Fraikin P, Danober L, Lesur B, Botez I, Caignard DH et al (2010) Ring-fused thiadiazines as core structures for the development of potent AMPA receptor potentiators. Curr Med Chem 17(30):3575–3582. CrossRefGoogle Scholar
  7. 7.
    Ward SE, Harries M (2010) Recent advances in the discovery of selective AMPA receptor positive allosteric modulators. Curr Med Chem 17(30):3503–3513CrossRefGoogle Scholar
  8. 8.
    Adler LA, Kroon RA, Stein M, Shahid M, Tarazi FI, Szegedi A, Schipper J, Cazorla P (2012) A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator org 26576 in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 72(11):971–977. CrossRefGoogle Scholar
  9. 9.
    Lynch G (2004) AMPA receptor modulators as cognitive enhancers. Curr Opin Pharmacol 4(1):4–11. CrossRefGoogle Scholar
  10. 10.
    O’Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES (2004) AMPA receptor potentiators for the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord 3(3):181–194CrossRefGoogle Scholar
  11. 11.
    Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G (2001) A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 21(5):484–487CrossRefGoogle Scholar
  12. 12.
    Alt A, Nisenbaum ES, Bleakman D, Witkin JM (2006) A role for AMPA receptors in mood disorders. Biochem Pharmacol 71(9):1273–1288. CrossRefGoogle Scholar
  13. 13.
    Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM (2009) Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience 159(1):283–295. CrossRefGoogle Scholar
  14. 14.
    Lauterborn JC, Palmer LC, Jia Y, Pham DT, Hou B, Wang W, Trieu BH, Cox CD et al (2016) Chronic ampakine treatments stimulate dendritic growth and promote learning in middle-aged rats. J Neurosci 36(5):1636–1646. CrossRefGoogle Scholar
  15. 15.
    Vignisse J, Steinbusch HW, Grigoriev V, Bolkunov A, Proshin A, Bettendorff L, Bachurin S, Strekalova T (2014) Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice. Eur Neuropsychopharmacol 24(2):309–320. CrossRefGoogle Scholar
  16. 16.
    Detrait ER, Hanon E, Dardenne B, Lamberty Y (2009) The inhibitory avoidance test optimized for discovery of cognitive enhancers. Behav Res Meth 41(3):805–811. CrossRefGoogle Scholar
  17. 17.
    Lermontova N, Lukoyanov N, Serkova T, Lukoyanova E, Bachurin S (1998) Effects of tacrine on deficits in active avoidance performance induced by AF64A in rats. Mol Chem Neuropathol 33(1):51–61CrossRefGoogle Scholar
  18. 18.
    Ader R, Weijnen JAWM, Moleman P (1972) Retention of a passive avoidance response as a function of the intensity and duration of electric shock. Psychon Sci 26(3):125–128. CrossRefGoogle Scholar
  19. 19.
    Webb B, Sali A (2014) Comparative protein structure modeling using Modeller. Current protocols in bioinformatics, John Wiley & Sons, Inc., 5.6.1–5.6.32.
  20. 20.
    Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948.
  21. 21.
    Harms JE, Benveniste M, Maclean JK, Partin KM, Jamieson C (2013) Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy. Neuropharmacology 64:45–52. CrossRefGoogle Scholar
  22. 22.
    Shen M-Y, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15:2507–2524. CrossRefGoogle Scholar
  23. 23.
    Davis IW, Raha K, Head MS, Baker D (2009) Blind docking of pharmaceutically relevant compounds using RosettaLigand. Protein Sci 18:1998–2002. CrossRefGoogle Scholar
  24. 24.
    Jakalian A, Jack DB, Bayly CI (2002) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem 23:1623–1641. CrossRefGoogle Scholar
  25. 25.
    Karlov DS, Lavrov MI, Palyulin VA, Zefirov NS (2018) MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulators. J Biomol Struct Dyn 36(10):2508–2516. CrossRefGoogle Scholar
  26. 26.
    Lavrov MI, Grigor’ev VV, Bachurin SO, Palyulin VA, Zefirov NS (2015) Novel bivalent positive allosteric modulators of AMPA receptor. Dokl Biochem Biophys 464:322–324. CrossRefGoogle Scholar
  27. 27.
    Lavrov MI, Lapteva VL, Grigor’ev VV, Palyulin VA, Bachurin SO, Zefirov NS (2012) Synthesis and AMPA-receptor modulating activity of benzodioxanecarboxylic and piperonylic acid derivatives. Pharm Chem J 46(2):92–95. CrossRefGoogle Scholar
  28. 28.
    Tikhonova IG, Lavrov MI, Palyulin VA, Zefirov NS (2004) The binding site for allosteric modulators of AMPA receptor. Dokl Biochem Biophys 399:351–353CrossRefGoogle Scholar
  29. 29.
    Radchenko EV, Karlov DS, Lavrov MI, Palyulin VA (2017) Structural requirements for molecular design of positive allosteric modulators of AMPA receptor. Mendeleev Communications 27(6):623–625. CrossRefGoogle Scholar
  30. 30.
    Karlov DS, Lavrov MI, Palyulin VA, Zefirov NS (2016) Pharmacophore analysis of positive allosteric modulators of AMPA receptors. Russ Chem Bull 65(2):581–587.
  31. 31.
    Kuznetsov AI, Basargin EB, Moskovkin AS, Ba MK, Miroshnichenko IV, Botnikov MY, Unkovskii BV (1985) Heteroadamantanes and their derivatives. 6. Synthesis and mass-spectrometric investigation of 5-mono- and 5,6-disubtituted 6-oxo-1,3-diazaadamantanes. Chem Heterocycl Compd 21(12):1382–1388. CrossRefGoogle Scholar
  32. 32.
    Kuznetsov AI, Basargin EB, Ba MK, Moskovkin AS, Miroshnichenko IV, Botnikov MY (1989) Heteroadamantanes and their derivatives. 7. Synthesis and mass-spectrometric study of functional derivatives of 5-mono- and 5,7-disubstituted 1,3-diazaadamantanes. Chem Heterocycl Compd 25(5):541–547. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of ChemistryLomonosov Moscow State UniversityMoscowRussian Federation
  2. 2.Institute of Physiologically Active CompoundsRussian Academy of SciencesChernogolovkaRussian Federation
  3. 3.Center for Computational and Data-Intensive Science and EngineeringSkolkovo Institute of Science and TechnologyMoscowRussian Federation
  4. 4.Federal State Budgetary Institution “Research Zakusov Institute of Pharmacology”MoscowRussian Federation

Personalised recommendations