Psychotropic activity of N-Aryl derivatives of (adamantan-1-yl)methylamine

The aim. To investigate the psychotropic activity of a series of N-aryl derivatives of (adamantan-1-yl)methylamine and to identify a compound with anxiolytic and anti-phobic effects, devoid of myorelaxant action and not impairing cognitive function.

Materials and methods. For the synthesis of target compounds, (adamantan-1-yl)methylamine, aryl bromides, and zero-valent palladium complexes were used. Product isolation was carried out using column chromatography on silica gel. Experiments were conducted on mice and adult male Wistar rats (12 months old). The psychotropic activity was assessed based on the results of a number of tests: “Open Field,” “Elevated Plus Maze,” “Novel Object Recognition”, and “Extrapolation Escape Task”. Anxiolytic activity was further studied in the Vogel conflict test. The assessment of possible myorelaxant effects and impact on motor coordination was performed using the “Rotarod” and “Horizontal-Bar” tests.

Results. A series of N-aryl-substituted (adamantan-1-yl)methylamines were synthesized under Buchwald–Hartwig amination conditions. During the optimization of reaction parameters, it was found that the standard catalytic system Pd(dba)₂ / BINAP in the presence of 1-bromo-4-fluorobenzene exhibited low efficiency (yield < 45 %). It was established that the use of the phosphine ligand DavePhos facilitates overcoming steric and electronic hindrances and provides a product yield of 74 %. In experiments on mice, compound XF (3 mg/kg) demonstrated significant anxiolytic and anti-phobic activity in the “Open Field” and “Elevated Plus Maze” tests. Regarding the effect on declarative memory, compound XF, along with XCl and XCN, showed a nootropic effect comparable to the reference drug phenotropil. In a second series of experiments on adult Wistar rats (12 months old), the anxiolytic effect of XF was confirmed in the “Open Field”, “Elevated Plus Maze”, and Vogel conflict tests. It was found that, unlike diazepam, compound XF does not cause a myorelaxant effect and does not impair motor coordination (Rotarod and Horizontal-Bar tests), while preserving cognitive functions.

Conclusion. The obtained results demonstrate that searching within the series of N-aryl derivatives of (adamantan-1-yl)methylamine for substances for in-depth investigation of psychotropic properties is promising. The introduction of a fluorine atom into the aryl fragment is considered a strategic tool for expanding the spectrum of pharmacological action of potential neuroprotectors.

1. Javaid SF, Hashim IJ, Hashim MJ Emmanuel Stip, Samad MA, Al Ahbabi A. Epidemiology of anxiety disorders: global burden and sociodemographic associations. Middle East Curr Psychiatry. 2023;30:44. DOI: 10.1186/s43045-023-00315-3

2. GBD 2023 Mental Disorder Collaborators. Updated trends in the global prevalence and burden of mental disorders, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023. Lancet. 2026;407:2040–2064. DOI: 10.1016/S0140-6736(26)00519-2

3. Bie F, Yan X, Xing J, Wang L, Xu Y, Wang G, Wang Q, Guo J, Qiao J, Rao Z. Rising global burden of anxiety disorders among adolescents and young adults: trends, risk factors, and the impact of socioeconomic disparities and COVID-19 from 1990 to 2021. Front Psychiatry. 2024;15:1489427. DOI: 10.3389/fpsyt.2024.1489427

4. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137–150. DOI: 10.1016/S2215-0366(21)00395-3

5. COVID-19 Mental Disorders Collaborators. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–1712. DOI: 10.1016/S0140-6736(21)02143-7

6. Edinoff AN, Nix CA, Hollier J, Sagrera CE, Delacroix BM, Abubakar T, Cornett EM, Kaye AM, Kaye AD. Benzodiazepines: Uses, Dangers, and Clinical Considerations. Neurol Int. 2021;13(4):594–607. DOI: 10.3390/neurolint13040059

7. Fernandes H, Novais C, Sousa-Pinto B, Soares-da-Silva P, Azevedo LF. Comparative Efficacy and Safety of Benzodiazepines in the Treatment of Patients with Generalized Anxiety Disorder: A Systematic Review and Network Meta-Analysis. Psychother Psychosom. 2025;94(5):373–388. DOI: 10.1159/000546269

8. Wanka L, Iqbal K, Schreiner PR. The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives. Chem Rev. 2013;113(5):3516−3604. DOI: 10.1021/cr100264t

9. Zoidis G, Fytas C, Papanastasiou I, Foscolos GB, Fytas G, Padalko E, De Clercq E, Naesens L, Neyts J, Kolocouris N. Heterocyclic rimantadine analogues with antiviral activity. Bioorg Med Chem. 2006;14(10):3341–3348. DOI: 10.1016/j.bmc.2005.12.056

10. Kolocouris N, Kolocouris A, Foscolos GB, Fytas G, Neyts J, Padalko E, Balzarini J, Snoeck R, Andrei G, De Clercq E. Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2. J Med Chem. 1996;39(17):3307–3318. DOI: 10.1021/jm950891z

11. Fytas G, Stamatiou G, Foscolos GB, Kolocouris A, Kolocouris N, Witvrouw M, Pannecouque C, De Clercq E. Synthesis and anti-HIV activity of some new aminoadamantane heterocycles. Bioorg Med Chem. Lett. 1997;7(Issue 14):1887. DOI: 10.1016/S0960-894X(97)00320-X

12. Stamatiou G, Foscolos GB, Fytas G, Kolocouris A, Kolocouris N, Pannecouque C, Witvrouw M, Padalko E, Neyts J, De Clercq E. Heterocyclic rimantadine analogues with antiviral activity. Bioorg Med Chem. 2003;11(24):5485–5492. DOI: 10.1016/j.bmc.2003.09.024

13. Balzarini J, Orzeszko-Krzesińska B, Maurin JK, Orzeszko A. Synthesis and anti-HIV studies of 2- and 3-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem. 2009;44(1):303–311. DOI: 10.1016/j.ejmech.2008.02.039

14. Balzarini J, Orzeszko-Krzesińska B, Maurin JK, Orzeszko A. Synthesis and anti-HIV studies of 2- and 3-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem. 2009;44(1):303–311. DOI: 10.1016/j.ejmech.2008.02.039

15. Printsevskaya SS, Solovieva SE, Olsufyeva EN, Mirchink EP, Isakova EB, De Clercq E, Balzarini J, Preobrazhenskaya MN. Structure-activity relationship studies of a series of antiviral and antibacterial aglycon derivatives of the glycopeptide antibiotics vancomycin, eremomycin, and dechloroeremomycin. J Med Chem. 2005;48(11):3885–3890. DOI: 10.1021/jm0500774

16. Šolaja BA, Opsenica D, Smith KS, Milhous WK, Terzic N, Opsenica I, Burnett JC, Nuss J, Gussio R, Bavari S. Novel 4-Aminoquinolines Active against Chloroquine-Resistant and Sensitive P. falciparum Strains that also Inhibit Botulinum Serotype A. J Med Chem. 2008;51:4388–4391. DOI: 10.1021/jm800737y

17. Magazanik LG, Buldakova SL, Samoilova MV, Gmiro VE, Mellor IR, Usherwood PN. Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives. J Physiol. 1997;505(Pt 3):655–663. DOI: 10.1111/j.1469-7793.1997.655ba.x

18. Zoidis G, Papanastasiou I, Dotsikas I, Sandoval A, Dos Santos RG, Papadopoulou-Daifoti Z, Vamvakides A, Kolocouris N, Felix R. The novel GABA adamantane derivative (AdGABA): design, synthesis, and activity relationship with gabapentin. Bioorg Med. Chem. 2005;13:2791–2798. DOI: 10.1016/j.bmc.2005.02.030

19. Bryans JS, Davies N, Gee NS, Dissanayake VU, Ratcliffe GS, Horwell DC, Kneen CO, Morrell AI, Oles RJ, O'Toole JC, Perkins GM, Singh L, Suman-Chauhan N, O'Neill JA. Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents. J Med Chem. 1998;41(11):1838–1845. DOI: 10.1021/jm970649n

20. Baxter A, Bent J, Bowers K, Braddock M, Brough S, Fagura M, Lawson M, McInally T, Mortimore M, Robertson M, Weaver R, Webborn P. Hit-to-Lead studies: the discovery of potent adamantane amide P2X7 receptor antagonists. Bioorg Med Chem Lett. 2003;13:4047–4050. DOI: 10.1016/j.bmcl.2003.08.034

21. Baraldi PG, Di Virgilio F, Romagnoli R. Agonists and antagonists acting at P2X7 receptor. Curr Top Med Chem. 2004;4(16):1707–1717. DOI: 10.2174/1568026043387223

22. Romagnoli R, Baraldi PG, Tabrizi MA, Bermejo J, Estévez F, Borgatti M, Gambari R. Design, synthesis, and biological evaluation of hybrid molecules containing alpha-methylene-gamma-butyrolactones and alpha-bromoacryloyl moieties. J Med Chem. 2005;48(24):7906–7910. DOI: 10.1021/jm058012o

23. Nelson DW, Gregg RJ, Kort ME, Perez-Medrano A, Voight EA, Wang Y, Grayson G, Namovic MT, Donnelly-Roberts DL, Niforatos W, Honore P, Jarvis MF, Faltynek CR, Carroll WA. Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists. J Med Chem. 2006;49(12):3659–3666. DOI: 10.1021/jm051202e

24. Kapoerchan VV, Knijnenburg AD, Niamat M, Spalburg E, de Neeling AJ, Nibbering PH, Mars-Groenendijk RH, Noort D, Otero JM, Llamas-Saiz AL, van Raaij MJ, van der Marel GA, Overkleeft HS, Overhand M. An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity. Chemistry. 2010;16(40):12174–12181. DOI: 10.1002/chem.201001686

25. Averin AD, Ulanovskaya MA, Kovalev VV, Beletskaya IP, Buryak AK, Orlinson BS, Novakov IA. Palladium-catalyzed amination of isomeric dihalobenzenes with 1- and 2-aminoadamantanes. Russ J Org Chem. 2010;46(1):64–72. EDN: QYXFDN

26. Averin AD, Ulanovskaya MA, Beletskaya IP, Buryak AK, Savel'ev EN, Orlinson BS, Novakov IA. Arylation of adamantanamines: ii.* palladium-catalyzed amination of dihalobenzenes with adamantylalkanamines. Russ J Org Chem. 2010;46(12):1790–1811. EDN: QYWABL

27. Murashkina AV, Averin AD, Panchenko SP, Abel AS, Maloshitskaya OA, Savelyev EN, Orlinson BS, Novakov IA, Correia CRD, Beletskaya IP. Comparison of the Catalytic Activities of Copper(I) Iodide and Copper Nanoparticles in the N-Arylation of Adamantane-Containing Amines. Russ J Org Chem. 2022;58:15–24.

28. Novakov IA, Orlinson BS, Alykova EA, Savelyev EN, Nebykov DN, Pichugin AM, Kravtsova MN, Kulikov AYu, Turko IP, Farkhutdinova EI. Study of the reduction of mono- and dinitriles of the adamantane series with a nickel-aluminum alloy. Izvestiya VolgSTU. Seria Chemistry and technology of organoelement monomers and polymeric materials. 2023;5(276):55–60. DOI: 10.35211/1990-5297-2023-5-276-55-60

29. Ukai T, Kawazura H, Ishii Y, Bonnet JJ, Ibers JA. Chemistry of dibenzylideneacetone-palladium(0) complexes: I. Novel tris(dibenzylideneacetone)dipalladium (solvent) complexes and their reactions with quinones. J Organomet. Chem. 1974;65(Issue 2):253–266. DOI: 10.1016/S0022-328X(74)80010-8

30. Panchenko SP, Abel AS, Averin AD, Maloshitskaya OA, Savelyev EN, Orlinson BS, Novakov IA, Beletskaya IP. Arylation of Adamantanamines: VIII. Optimization of the Catalytic System for Copper-Catalyzed Arylation of Adamantane-Containing Amines. Russ J Org Chem. 2017;53(10):1497–1504. DOI: 10.1134/S1070428017100025