Anastasiya A. KOTLYAROVA, Konstantin Yu. PONOMAREV, Ekaterina A. MOROZOVA, Dina V. KORCHAGINA, Evgeniy V. SUSLOV, Alla V. PAVLOVA, Tatyana G. TOLSTIKOVA, Konstantin P. VOLCHO, Nariman F. SALAKHUTDINOV

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

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 (aftersingle dosing and a 7-day administration). It has been shown for the first time that derivatives of monoterpenoidswith 3,7-diazabicyclo[3.3.1]nonane moiety containing methyl substituents at positions 1 and 5 have a stimulatoryeffect 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 mosteffective in increasing the duration of running and swimming at a dose of 100 mg/kg after single intragastricadministration. It has been also established that the LD50 for these compounds exceeds 1,000 mg/kg.

PDF

___

[1] Gorchakova NA, Gudivok YaS, Gunina LM. Farmakologiya sporta. Kiev, Olimpijskaya literatura, 2010.
[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] Shustov EB, Karkishchenko NN, Ujba VV, Karkishchenko VN. Ocherki sportivnoj farmakologii. Tom 1. Vektory ekstrapolyacii. M., SPb. Ajsing, 2014
[4] Zherdev VP, Kolyvanov GB, Litvin AA. Biotransformaciya i farmakokinetika proizvodnyh adamantana. Farmakokinetika i farmakodinamika. 2012; 1: 18–24.
[5] Morozov IS, Petrov VI, Sergeeva SA. Farmakologiya adamantanov. Volgograd: Volgogradskaya medicinskaya akademiya, 2001.
[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] 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] 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] Amyaga NV. Eksperimental'noe izuchenie aktoprotektornyh svojstv med'soderzhashchih proizvodnyh nikotinovoj kisloty. Fundamental'nye Aspekty Psihicheskogo Zdorov'ya. 2018; 1: 23–25.
[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] 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] Docherty JR. Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Br J Pharmacol. 2008; 154: 606–622. [CrossRef]
[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] Salakhutdinov NF, Volcho KP, Yarovaya OI. Monoterpenes as a renewable source of biologically active compounds. Pure Appl Chem. 2017; 89: 1105–1117. [CrossRef]
[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] 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] 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] 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] 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] Tomassoli I, Gündisch D. Bispidine as a Privileged Scaffold. Curr Top Med Chem. 2016; 16: 1314–1342.
[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] 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] Heidmann B, Gatfield J, Roch C, et al. Discovery of Highly Potent Dual Orexin Receptor Antagonists via a ScaffoldHopping Approach. ChemMedChem. 2016; 11: 2132–2146. [CrossRef]
[24] Scammell TE, Winrow CJ. Orexin Receptors: Pharmacology and Therapeutic Opportunities. Annu Rev Pharmacol Toxicol. 2011; 51: 243–266. [CrossRef]
[25] Ebrahim IO, Howard RS, Kopelman MD, et al. The hypocretin/orexin system. J R Soc Med. 2002; 95: 227–230.
[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] 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] 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] 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] Habriev RU. Rukovodstvo po eksperimental'nomu (doklinicheskomu) izucheniyu novyh farmakologicheskih veshchestv. 2 izd. M. Izdatel'stvo «Medicina» 2005.
[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] 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] 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] 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] Mironov AN, Bunyatyan ND. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv. Chast' pervaya. M. Grif i K. 2012.