The effect of 3,7-diazabicyclo[3.3.1]nonanes containing monoterpenoid moieties on the physical activity of mice

Abstract

The aim of this work is to study the effect of agents combining fragments of monoterpenoids and 3,7-diazabicyclo[3.3.1]nonane (bispidine) on the performance of mice. Physical endurance was studied using two tests: exhaustive swimming with a load of 7% of body weight (after single dosing) and exhaustive treadmill running (after single dosing and a 7-day administration). It has been shown for the first time that derivatives of monoterpenoids with 3,7-diazabicyclo[3.3.1]nonane moiety containing methyl substituents at positions 1 and 5 have a stimulatory effect on the performance of mice, which exceeds the effect of the reference drug bromantane after single dosing. Compound K1-458, which contains (–)-myrtenal residues linked to a bispidine fragment via amino groups, is the most effective in increasing the duration of running and swimming at a dose of 100 mg/kg after single intragastric administration. It has been also established that the LD50 for these compounds exceeds 1,000 mg/kg.

Keywords

• Actoprotectors
• treadmill
• bromantane
• monoterpenoids
• bispidine

References

1. [1] Gorchakova NA, Gudivok YaS, Gunina LM. Farmakologiya sporta. Kiev, Olimpijskaya literatura, 2010.
2. [2] Oliynyk S, Oh S. The Pharmacology of Actoprotectors: Practical Application for Improvement of Mental and Physical Performance. Biomol Ther. 2012; 20: 446–456. [CrossRef]
3. [3] Shustov EB, Karkishchenko NN, Ujba VV, Karkishchenko VN. Ocherki sportivnoj farmakologii. Tom 1. Vektory ekstrapolyacii. M., SPb. Ajsing, 2014
4. [4] Zherdev VP, Kolyvanov GB, Litvin AA. Biotransformaciya i farmakokinetika proizvodnyh adamantana. Farmakokinetika i farmakodinamika. 2012; 1: 18–24.
5. [5] Morozov IS, Petrov VI, Sergeeva SA. Farmakologiya adamantanov. Volgograd: Volgogradskaya medicinskaya akademiya, 2001.
6. [6] Wanka L, Iqbal K, Schreiner PR. The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem Rev. 2013; 113: 3516–3604. [CrossRef]
7. [7] Mozhaitsev ES, Zakharenko AL, Suslov EV, et al. Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments. Anticancer Agents Med Chem. 2019; 19(4): 463- 472. [CrossRef]
8. [8] Zakharenko AL, Mozhaitsev ES, Suslov EV, et al. Synthesis and Inhibitory Properties of Imines Containing Monoterpenoid and Adamantane Fragments Against DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1 (Tdp1). Chem Nat Compd. 2018; 54: 672–676. [CrossRef]

9. [9] Amyaga NV. Eksperimental'noe izuchenie aktoprotektornyh svojstv med'soderzhashchih proizvodnyh nikotinovoj kisloty. Fundamental'nye Aspekty Psihicheskogo Zdorov'ya. 2018; 1: 23–25.
10. [10] Studencov EP, Ramsh SM, Kazurova NG, Neporozhneva OV, Garabadzhiu AV, Kochina TA, Voronkov MG, Kuznecov VA, Krivorotov DV. Adaptogeny i rodstvennye gruppy lekarstvennyh preparatov - 50 let poiskov. Obzory Po Klinicheskoj Farmakologii I Lekarstvennoj Terapii. 2013; 11: 3–43.
11. [11] Salimgareeva MK, Yamidanov RS, Vakhitova YV, et al. Mechanisms of action of ladasten: activation of gene expression for neurotrophins and mitogen-activated kinases. Bull Exp Biol Med. 2012; 152: 313–317.
12. [12] Docherty JR. Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Br J Pharmacol. 2008; 154: 606–622. [CrossRef]
13. [13] Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 2016; 79: 629–661. [CrossRef]
14. [14] Salakhutdinov NF, Volcho KP, Yarovaya OI. Monoterpenes as a renewable source of biologically active compounds. Pure Appl Chem. 2017; 89: 1105–1117. [CrossRef]
15. [15] Tsuzuki K, Xing H, Ling J, et al. Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission. J Neurosci Off J Soc Neurosci. 2004; 24: 762–771. [CrossRef]
16. [16] Silva RO, Salvadori MS, Sousa FBM, et al. Evaluation of the anti-inflammatory and antinociceptive effects of myrtenol, a plant-derived monoterpene alcohol, in mice. Flavour Fragr J. 2014; 29: 184–192. [CrossRef]
17. [17] Silva MIG, Silva MAG, de Aquino Neto MR, et al. Effects of isopulegol on pentylenetetrazol-induced convulsions in mice: possible involvement of GABAergic system and antioxidant activity. Fitoterapia. 2009; 80: 506–513. [CrossRef]
18. [18] Rekha KR, Selvakumar GP, Sethupathy S, et al. Geraniol ameliorates the motor behavior and neurotrophic factors inadequacy in MPTP-induced mice model of Parkinson’s disease. J Mol Neurosci MN. 2013; 51: 851–862. [CrossRef]
19. [19] Rekha KR, Selvakumar GP. Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson’s disease. Chem Biol Interact. 2014; 217: 57–66. [CrossRef]
20. [20] Tomassoli I, Gündisch D. Bispidine as a Privileged Scaffold. Curr Top Med Chem. 2016; 16: 1314–1342.
21. [21] Amos GJ, Abrahamsson C, Duker G, et al. Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential. Cardiovasc Res. 2001; 49: 351–360. [CrossRef]
22. [22] Bunnelle W, Cristina D, Daanen J, et al. Diazabicyclic CNS active agents. US20030225268A1, https://patents.google.com/patent/US20030225268A1/en (accessed on 25 June 2019).
23. [23] Heidmann B, Gatfield J, Roch C, et al. Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach. ChemMedChem. 2016; 11: 2132–2146. [CrossRef]
24. [24] Scammell TE, Winrow CJ. Orexin Receptors: Pharmacology and Therapeutic Opportunities. Annu Rev Pharmacol Toxicol. 2011; 51: 243–266. [CrossRef]
25. [25] Ebrahim IO, Howard RS, Kopelman MD, et al. The hypocretin/orexin system. J R Soc Med. 2002; 95: 227–230.
26. [26] Ponomarev K, Pavlova A, Suslov E, et al. Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties. Med Chem Res. 2015; 24: 4146–4156. [CrossRef]
27. [27] Khomenko TM, Zarubaev VV, Orshanskaya IR, et al. Anti-influenza activity of monoterpene-containing substituted coumarins. Bioorg Med Chem Lett. 2017; 27: 2920–2925. [CrossRef]
28. [28] Lin G, Duan W, Liu H, et al. Synthesis and Bioactivity of N-(4-(N′-Substituted Sulfamoyl)Phenyl)Myrtenamides Containing a Heterocycle. Chem Nat Compd. 2018; 54: 56–62. [CrossRef]
29. [29] Voronina Т.А., Kapitsa I.G., Ivanova Е.А. A comparative study of the effects of mexidolum and mildronatum on the physical performance of experimental animals S.S. Korsakov Journal of Neurology and Psychiatry. 2017; 117: 71–74. [article in Russian with an abstract in English] [CrossRef]
30. [30] Habriev RU. Rukovodstvo po eksperimental'nomu (doklinicheskomu) izucheniyu novyh farmakologicheskih veshchestv. 2 izd. M. Izdatel'stvo «Medicina» 2005.
31. [31] Karkishchenko VN, Fokin YuV, Kazakova LH, Alimkina OV, Kasinskaya NV. Metodiki izucheniya fiziologicheskih funkcij laboratornyh zhivotnyh dlya doklinicheskih issledovanij v sportivnoj medicine. Biomedicina. 2012; 4:15–21.
32. [32] Karkishchenko NN. Farmakologiya processov adaptacii i perenosimosti predel'nyh nagruzok v sporte i rezhimah raboty «do otkaza»: vtoroj tajm dlya dzhenerikov. Biomedicina. 2010; 4: 6–23.
33. [33] Dougherty JP, Springer DA, Gershengorn MC. The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse. J Vis Exp. 2016; 31:(111). [CrossRef]
34. [34] Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977; 229: 327–336.
35. [35] Mironov AN, Bunyatyan ND. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv. Chast' pervaya. M. Grif i K. 2012.