Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula.

Department of Chemistry Faculty of Science Charles University Prague 128 43 Prague 2 Czech Republic

Department of Chemistry South West University Neofit Rilski 2700 Blagoevgrad Bulgaria

Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China

Institute of Organic Chemistry With Centre of Phytochemistry Bulgarian Academy of Sciences Acad G Bontchev Str Bl 9 1113 Sofia Bulgaria

Krestov's Institute of Solution Chemistry Russian Academy of Sciences 153045 Ivanovo Russia

See more in PubMed

ACD/ChemSketch program. https://eduinf.waw.pl/che/inne/prgchem/pages/chsk_eng.pdf

Adolfsson R, Gottfries CG, Roos BE, Winblad B (1979) Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry 135(3):216–223. https://doi.org/10.1192/bjp.135.3.216 PubMed DOI

Alves Galvão MG, Rocha Crispino Santos MA, Alves da Cunha AJ (2014) Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD002745.pub4 PubMed DOI PMC

Anand R, Gill KD, Mahdi AA (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 76:27–50. https://doi.org/10.1016/j.neuropharm.2013.07.004 PubMed DOI

Andrés A, Rosés M, Ràfols C, Bosch E, Espinosa S, Segarra V, Huerta JM (2015) Setup and validation of shake-flask procedures for the determination of partition coefficients (log P) from low drug amounts. Eur J Pharm Sci 76:181–191. https://doi.org/10.1016/j.ejps.2015.05.008 PubMed DOI

Arciniegas DB, Frey KL, Anderson CA, Brousseau KM, Harris SN (2004) Amantadine for neurobehavioural deficits following delayed post-hypoxic encephalopathy. Brain Inj 18(12):1309–1318. https://doi.org/10.1080/02699050410001720130 PubMed DOI

Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’sdisease. Lancet 377(9770):1019–1031. https://doi.org/10.1016/S0140-6736(10)61349-9 PubMed DOI

Borodin VA, Kozlovsky EV, Vasilev VP (1982) Computer analysis of the results of calorimetric measurements in study on complex equilibriums in solutions. Russian J Inorganic Chem 27:2169–2172

Chiang K, Koo EH (2014) Emerging therapeutics for Alzheimer’s disease. Annu Rev Pharmacol Toxicol 54:381–405. https://doi.org/10.1146/annurev-pharmtox-011613-135932 PubMed DOI

Davies WL, Grunert RR, Haff RF, Mcgahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE (1964) Antiviral activity of 1-adamantanamine (Amantadine). Science 144(3620):862–863. https://doi.org/10.1126/science.144.3620.862 PubMed DOI

Di Cagno M, Bibi HA, Bauer-Brandl A (2015) New biomimetic barrier Permeapad PubMed DOI

Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF (2015) Vascular dysfunction in the pathogenesis of Alzheimer’s disease—a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol Dis 82:593–606. https://doi.org/10.1016/j.nbd.2015.08.014 PubMed DOI

Di Marco B, Bonaccorso CM, Aloisi E, Antoni S, Catania MV (2016) Neuro-inflammatory mechanisms in developmental disorders associated with intellectual disability and autism spectrum disorder: a neuro-immune perspective. CNS Neurol Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 15(4):448–463. https://doi.org/10.2174/1871527315666160321105039 DOI

Di L, Kerns EH (2015) Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization. Academic press NY

Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–62 PubMed

Doody RS, Tariot PN, Pfeiffer E, Olin JT, Graham SM (2007) Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimer’s Dementia 3(1):7–17. https://doi.org/10.1016/j.jalz.2006.10.004 PubMed DOI

Faller P (2009) Copper and zinc binding to amyloid-β: coordination, dynamics, aggregation. Reactivity Metal-Ion Trans ChemBioChem 10(18):2837–2845. https://doi.org/10.1002/cbic.200900321 DOI

Gamdzyk M, Ziembowicz A, Bratek E, Salinska E (2016) Combining hypobaric hypoxia or hyperbaric oxygen postconditioning with memantine reduces neuroprotection in 7-day-old rat hypoxia-ischemia. Pharmacol Rep 68(5):1076–1083. https://doi.org/10.1016/j.pharep.2016.06.009 PubMed DOI

Giuffrida ML, Grasso G, Ruvo M, Pedone C, Saporito A, Marasco D, Pignataro B, Cascio C, Copani A, Rizzarelli E (2007) Aβ (25–35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity. J Neurosci Res 85(3):623–633. https://doi.org/10.1002/jnr.21135 PubMed DOI

Heiss WD, Szelies B, Kessler J, Herholz K (1991) Abnormalities of energy metabolism in Alzheimer’s disease studied with PET a. Ann N Y Acad Sci 640(1):65–71. https://doi.org/10.1111/j.1749-6632.1991.tb00192.x PubMed DOI

Higuchi T (1965) A phase solubility technique. Adv Anal Chem Instrum 4:117–211

Hu J, Zhao TZ, Chu WH, Luo CX, Tang WH, Yi L, Feng H (2010) Protective effects of 20-hydroxyecdysone on CoCl PubMed DOI

Hubsher G, Haider M, Okun MS (2012) Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology 78(14):1096–1099. https://doi.org/10.1212/WNL.0b013e31824e8f0d PubMed DOI

Johnson JW, Kotermanski SE (2006) Mechanism of action of memantine. Curr Opin Pharmacol 6(1):61–67. https://doi.org/10.1016/j.coph.2005.09.007 PubMed DOI

Kim JH, Lee HW, Hwang J, Kim J, Lee MJ, Han HS, Lee WH, Suk K (2012) Microglia-inhibiting activity of Parkinson’s disease drug amantadine. Neurobiol Aging 33(9):2145–2159. https://doi.org/10.1016/j.neurobiolaging.2011.08.011 PubMed DOI

Knorr R, Trzeciak A, Bannwarth W, Gillessen D (1989) New coupling reagents in peptide chemistry. Tetrahedron Lett 30(15):1927–1930 DOI

Korenman IM (1977) Ekstraktsiya v analize organicheskikh veshchestv. Extraction in the analysis of organic compounds. Moscow, Khimiya, pp 78–84

Kornhuber J, Weller M, Schoppmeyer K, Riederer P (1994) Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl 43:91–104 PubMed

Leon R, Garcia AG, Marco-Contelles J (2013) Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 33(1):139–189. https://doi.org/10.1002/med.20248 PubMed DOI

Liang GD, Zhang YW, Lin DE (2010) Synthesis of memantine derivatives. Chinese J Synthetic Chem 4:38

Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discovery 5(2):160. https://doi.org/10.1038/nrd1958 PubMed DOI

Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang L, Zhang TT, Du GH (2012) Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC medicine 10(1):105. https://doi.org/10.1186/1741-7015-10-105 PubMed DOI PMC

Liu QS, Jiang HL, Wang Y, Wang LL, Zhang JX, He CH, Shao S, Zhang TT, Xing JG, Liu R (2018) Total flavonoid extract from Dracoephalum moldavica L. attenuates β-amyloid-induced toxicity through anti-amyloidogenesic and neurotrophic pathways. Life Sci 193:214–225. https://doi.org/10.1016/j.lfs.2017.10.041 PubMed DOI

Makarewicz D, Sulejczak D, Duszczyk M, Małek M, Słomka M, Lazarewicz JW (2014) Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia. Folia Neuropathol 52(3):270–284. https://doi.org/10.5114/fn.2014.45568 PubMed DOI

Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639. https://doi.org/10.1038/nature02621 PubMed DOI PMC

Müller T, Kuhn W, Möhr JD (2019) Evaluating ADS5102 (amantadine) for the treatment of Parkinson’s disease patients with dyskinesia. Expert Opin Pharmacother 20(10):1181–1187. https://doi.org/10.1080/14656566.2019.1612365 PubMed DOI

Multhaup G, Schlicksupp A, Hesse L, Beher D, Ruppert T, Masters CL, Beyreuther K (1996) The amyloid precursor protein of Alzheimer’s disease in the reduction of copper (II) to copper (I). Science 271(5254):1406–1409. https://doi.org/10.1126/science.271.5254.1406 PubMed DOI

Pan X, Kaminga AC, Wen S, Wu X, Acheampong K, Liu A (2019) Dopamine and dopamine receptors in Alzheimer’s disease: a systematic review and network meta-analysis. Front Aging Neurosci 11:175. https://doi.org/10.3389/fnagi.2019.00175 PubMed DOI PMC

Parfenova H, Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, Leffler CW (2006) Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection. Am J Physiol-Cell Physiol 290(5):C1399–C1410. https://doi.org/10.1152/ajpcell.00386.2005 PubMed DOI

Parsons CG, Stöffler A, Danysz W (2007) Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacology 53(6):699–723. https://doi.org/10.1016/j.neuropharm.2007.07.013 PubMed DOI PMC

Perlovich GL, Volkova TV (2018) Sublimation thermodynamics aspects of adamantane and memantine derivatives of sulfonamide molecular crystals. Phys Chem Chem Phys 20(30):19784–19791. https://doi.org/10.1039/C8CP03716G PubMed DOI

Perlovich GL, Ryzhakov AM, Tkachev VV, Proshin AN (2015) Adamantane derivatives of sulfonamide molecular crystals: structure, sublimation thermodynamic characteristics, molecular packing, and hydrogen bond networks. CrystEngComm 17(4):753–763. https://doi.org/10.1039/C4CE02076F DOI

Perlovich GL, Volkova TV, Sharapova AV, Kazachenko VP, Strakhova NN, Proshin AN (2016) Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents. Phys Chem Chem Phys 18(13):9281–9294. https://doi.org/10.1039/C6CP00379F PubMed DOI

Po HN, Senozan NM (2001) The Henderson-Hasselbalch equation: its history and limitations. J Chem Educ 78(11):1499–1503. https://doi.org/10.1021/ed078p1499 DOI

Raevsky OA, Grigor’ev VJ, Trepalin SV (1999) HYBOT program package. Registration by Russian State Patent Agency (990090)

Ramakrishnan MA (2016) Determination of 50% endpoint titer using a simple formula. World J Virol 5(2):85. https://doi.org/10.5501/wjv.v5.i2.85 PubMed DOI PMC

Rogawski MA, Wenk GL (2003) The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 9(3):275–308. https://doi.org/10.1111/j.1527-3458.2003.tb00254.x PubMed DOI PMC

Saganuwan SA (2011) A modified arithmetical method of Reed and Muench for determination of a relatively ideal median lethal dose (LD50). Afr J Pharmacy Pharmacol 5(12):1543–1546. https://doi.org/10.5897/AJPP2019.5070 DOI

Sawikr Y, Yarla NS, Peluso I, Kamal MA, Aliev G, Bishayee A (2017) Neuroinflammation in Alzheimer’s disease: the preventive and therapeutic potential of polyphenolic nutraceuticals. Adv Protein Chem Struct Biol 108:33–57. https://doi.org/10.1016/bs.apcsb.2017.02.001 PubMed DOI

Scatton B, Cheramy A, Besson MJ, Glowinski J (1970) Increased synthesis and release of dopamine in the striatum of the rat after amantadine treatment. Eur J Pharmacol 13(1):131–133 DOI

Schmitt HP (2005) On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease. Med Hypotheses 65(2):259–265. https://doi.org/10.1016/j.mehy.2005.03.011 PubMed DOI

Sharp CD, Hines I, Houghton J, Warren A, Jackson TH, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS (2003) Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol-Heart Circulatory Physiol 285(6):H2592–H2598. https://doi.org/10.1152/ajpheart.00520.2003 DOI

Shibnev VA, Garaev TM, Finogenova MP, Shevchenko ES, Burtseva EI (2012) Some pathways to overcoming drug resistance of influenza a virus to adamantane derivatives. Pharm Chem J 46(1):1–5. https://doi.org/10.1007/s11094-012-0723-2 DOI

Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer’s disease amyloid β peptide. Biochim Biophys Acta BBA-Biomembranes 1768(8):1976–1990. https://doi.org/10.1016/j.bbamem.2007.02.002 PubMed DOI

Spilovska K, Zemek F, Korabecny J, Nepovimova E, Soukupa O, Windischd M, Kuca K (2016) Adamantane–a lead structure for drugs in clinical practice. Curr Med Chem 23(29):3245–3266. https://doi.org/10.2174/0929867323666160525114026 PubMed DOI

Tacutu R, Budovsky A, Yanai H, Fraifeld VE (2011) Molecular links between cellular senescence, longevity and age-related diseases–a systems biology perspective. Aging Albany NY 3(12):1178–1191. https://doi.org/10.18632/aging.100413 PubMed DOI PMC

Tai KK, Truong DD (2013) Amiloride but not memantine reduces neurodegeneration, seizures and myoclonic jerks in rats with cardiac arrest-induced global cerebral hypoxia and reperfusion. PLoS ONE 8(4):e60309. https://doi.org/10.1371/journal.pone.0060309 PubMed DOI PMC

Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84. https://doi.org/10.1016/j.biocel.2006.07.001 PubMed DOI

Varier KM, Sumathi T (2019) Hinokitiol offers neuroprotection against 6-OHDA-induced toxicity in SH-SY5Y neuroblastoma cells by downregulating mRNA expression of MAO/α-Synuclein/LRRK2/PARK7/PINK1/PTEN Genes. Neurotox Res 35(4):945–954. https://doi.org/10.1007/s12640-018-9988-x PubMed DOI

Voronin AP, Volkova TV, Ilyukhin AB, Trofimova TP, Perlovich GL (2018) Structural and energetic aspects of adamantane and memantine derivatives of sulfonamide molecular crystals: experimental and theoretical characterisation. CrystEngComm 20(25):3476–3489. https://doi.org/10.1039/C8CE00426A DOI

Zeidán-Chuliá F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JCF (2014) The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev 38:160–172. https://doi.org/10.1016/j.neubiorev.2013.11.008 PubMed DOI

Zhao J, Peng L, Zheng W, Wang R, Zhang L, Yang J, Chen H (2015) Chemically bonding of amantadine with gardenamide a enhances the neuroprotective effects against corticosterone-induced insults in PC12 cells. Int J Mol Sci 16(9):22795–22810. https://doi.org/10.3390/ijms160922795 PubMed DOI PMC

Zheng H, Fridkin M, Youdim M (2014) From single target to multitarget/network therapeutics in Alzheimer’s therapy. Pharmaceuticals 7(2):113–135. https://doi.org/10.3390/ph7020113 PubMed DOI PMC

Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug