JOURNAL OF THE CZECH PHARMACEUTICAL SOCIETY AND THE SLOVAK PHARMACEUTICAL SOCIETY

Čes. slov. farm. 2018, 67(2):51-58 | DOI: 10.36290/csf.2018.007

Melatonin as a structural template in the development of novel drugs for neurodegenerative disorders

Jan Korábečný1,2
1 Centrum biomedicínského výzkumu Fakultní nemocnice Hr. Králové, Hradec Králové
2 Katedra toxikologie a vojenské farmacie, Fakulta vojenského zdravotnictví, Hradec Králové

Melatonin is a key regulatory hormone produced mainly in the pineal gland. In the recent years, melatonin contribution to neurodegenerative disorders has dramatically increased when inspecting its favorable pharmacological profile. Its levels were found to be decreased during aging. Data from clinical studies point out to its positive outcome not only in improving the quality of sleep but it also exerts anti-inflammatory and antioxidant profile. Moreover, it was found as an effective neuroprotective agent. Current study summarizes the experimental data from basic research of medicinal chemistry field devoted to melatonin. Particular emphasis is directed toward melatonin derivatives with multipotent profile affecting concomitantly several pathological hallmarks of the neurodegenerative disorders.

Keywords: acetylcholinesterase; Alzheimer's disease; antioxidant; butyrylcholinesterase; melatonin; neurodegenerative disorders
Grants and funding:

Práce byla podpořena Dlouhodobým záměrem rozvoje a organizace - zdravotnická problematika ZHN (Fakulta vojenského zdravotnictví), finančními prostředky Fakultní nemocnice Hradec Králové (č. 00179906) a projektem Ministerstva zdravotnictví ČR s reg. č. 15-30954A.

Received: February 28, 2018; Accepted: April 9, 2018; Published: February 1, 2018  Show citation

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Korábečný J. Melatonin as a structural template in the development of novel drugs for neurodegenerative disorders. Čes. slov. farm. 2018;67(2):51-58. doi: 10.36290/csf.2018.007.
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    References

    1. Menendez-Pelaez A., Reiter R. J. Distribution of Melatonin in Mammalian Tissues: The Relative Importance of Nuclear versus Cytosolic Localization. J. Pineal Res. 1993; 15, 59-69. Go to original source... Go to PubMed...
    2. Sánchez-Barceló E. J., Mediavilla M. D., Tan D. X., Reiter R. J. Clinical Uses of Melatonin: Evaluation of Human Trials. Curr. Med. Chem. 2010; 17, 2070-2095. Go to original source... Go to PubMed...
    3. Hardeland R. Melatonin Metabolism in the Central Nervous System. Curr. Neuropharmacol. 2010; 8, 168-181. Go to original source...
    4. Albertini M. C., Radogna F., Accorsi A., Uguccioni F., Paternoster L., Cerella C., de Nicola M., D'Alessio M., Bergamaschi A., Magrini A., Ghibelli L. Intracellular pro-oxidant activity of melatonin deprives U937 cells of reduced glutathione without affecting glutathione peroxidase activity. Ann. N. Y. Acad. Sci. 2006; 1091, 10-16. Go to original source... Go to PubMed...
    5. Reiter R. J., Acuña-Castroviejo D., Tan D. X., Burkhardt S. Free radical-mediated molecular damage. mechanisms for the protective actions of melatonin in the central nervous system. Ann. N. Y. Acad. Sci. 2001; 939, 200-215. Go to original source...
    6. Reiter R. J., Tan D., Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech. Ageing Dev. 2002; 123, 1007-1019. Go to original source... Go to PubMed...
    7. Reiter R. J., Tan D.-X., Mayo J. C., Sainz R. M., Leon J., Czarnocki Z. Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochim. Pol. 2003; 50, 1129-1146. Go to original source...
    8. Hardeland R. Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms. J. Pineal Res. 2013; 55, 325-356. Go to original source... Go to PubMed...
    9. Hardeland R., Coto-Montes A. New vistas on oxidative damage and aging. Open Biol. J. 2010; 3, 39-52. Go to original source...
    10. Armstrong S. M., Redman J. R. Melatonin: a chronobiotic with anti-aging properties? Med. Hypotheses 1991; 34, 300-309. Go to original source... Go to PubMed...
    11. Morphy R., Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 2005; 48, 6523-6543. Go to original source... Go to PubMed...
    12. Spilovska K., Zemek F., Korabecny J., Nepovimova E., Soukup O., Windisch M., Kuca K. Adamantane - a lead structure for drugs in clinical practice. Curr. Med. Chem. 2016; 23, 3245-3266. Go to original source... Go to PubMed...
    13. Davies P., Maloney A. J. Selective Loss of central cholinergic neurons in Alzheimer's disease. Lancet 1976; 2, 1403. Go to original source... Go to PubMed...
    14. Zemek F., Drtinova L., Nepovimova E., Sepsova V., Korabecny J., Klimes J., Kuca K. Outcomes of Alzheimer's disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin. Drug Saf. 2014; 13, 759-774.
    15. Korábečný J., Nepovimová E., Cikánková T., Špilovská K., Vašková L., Mezeiová E., Kuča K., Hroudová J. Newly developed drugs for Alzheimer's disease in relation to energy metabolism, cholinergic and monoaminergic neurotransmission. Neuroscience 2018; 370, 191-206. Go to original source... Go to PubMed...
    16. Hardy J., Selkoe D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297, 353-356. Go to original source... Go to PubMed...
    17. Liao D., Miller E. C., Teravskis P. J. Tau acts as a mediator for Alzheimer's disease-related synaptic deficits. Eur. J. Neurosci. 2014; 39, 1202-1213. Go to original source... Go to PubMed...
    18. Bolognin S., Drago D., Messori L., Zatta P. Chelation therapy for neurodegenerative diseases. Med. Res. Rev. 2009; 29, 547-570. Go to original source... Go to PubMed...
    19. Rosini M., Simoni E., Milelli A., Minarini A., Melchiorre C. Oxidative stress in Alzheimer's disease: Are we connecting the dots? J. Med. Chem. 2014; 57, 2821-2831. Go to original source... Go to PubMed...
    20. Korábecný J., Hrubá E., Soukup O., Zemek F., Musílek K., Nepovímová E., Spilovská K., Opletalová V., Kuca K. Intended pharmacotherapeutical approaches of Alzheimer's disease therapy. Ces. slov. Farm. 2012; 61, 4-10.
    21. Cavalli A., Bolognesi M. L., Minarini A., Rosini M., Tumiatti V., Recanatini M., Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008; 51, 347-372. Go to original source... Go to PubMed...
    22. Prati F., Cavalli A., Bolognesi M. L. Navigating the chemical space of multitarget-directed ligands: from hybrids to fragments in Alzheimer's disease. Mol. Basel Switz. 2016; 21, 466. Go to original source... Go to PubMed...
    23. Muñoz-Ruiz P., Rubio L., García-Palomero E., Dorronsoro I., del Monte-Millán M., Valenzuela R., Usán P., de Austria C., Bartolini M., Andrisano V., Bidon-Chanal A., Orozco M., Luque F. J., Medina M., Martínez A. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. J. Med. Chem. 2005; 48, 7223-7233. Go to original source... Go to PubMed...
    24. Inestrosa N. C., Alvarez A., Pérez C. A., Moreno R. D., Vicente M., Linker C., Casanueva O. I., Soto C., Garrido J. Acetylcholinesterase Accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 1996; 16, 881-891. Go to original source... Go to PubMed...
    25. Korábečný J., Spilovská K., Benek O., Musílek K., Soukup O., Kuča K. Tacrine and its derivatives in the therapy of Alzheimers disease. Ces. slov. Farm. 2012; 61, 210-221.
    26. Recanatini M., Cavalli A., Belluti F., Piazzi L., Rampa A., Bisi A., Gobbi S., Valenti P., Andrisano V., Bartolini M., Cavrini V. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory Activity, QSAR, and structure-based CoMFA of tacrine analogues. J. Med. Chem. 2000; 43, 2007-2018. Go to original source... Go to PubMed...
    27. Nordberg A., Ballard C., Bullock R., Darreh-Shori T., Somogyi M. A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. Prim. Care Companion CNS Disord. 2013; 15. Go to original source... Go to PubMed...
    28. Minic J., Chatonnet A., Krejci E., Molgó J. Butyrylcholinesterase and acetylcholinesterase activity and quantal transmitter release at normal and acetylcholinesterase knockout mouse neuromuscular junctions. Br. J. Pharmacol. 2003; 138, 177-187. Go to original source... Go to PubMed...
    29. Rodríguez-Franco M. I., Fernández-Bachiller M. I., Pérez C., Hernández-Ledesma B., Bartolomé B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem. 2006; 49, 459-462. Go to original source... Go to PubMed...
    30. Sofic E., Rimpapa Z., Kundurovic Z., Sapcanin A., Tahirovic I., Rustembegovic A., Cao G. Antioxidant capacity of the neurohormone melatonin. J. Neural Transm. Vienna Austria 1996 2005; 112, 349-358. Go to original source... Go to PubMed...
    31. Di L., Kerns E. H., Fan K., McConnell O. J., Carter G. T. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem. 2003; 38, 223-232. Go to original source... Go to PubMed...
    32. López-Iglesias B., Pérez C., Morales-García J. A., Alonso-Gil S., Pérez-Castillo A., Romero A., López M. G., Villarroya M., Conde S., Rodríguez-Franco M. I. New melatonin-n,n-dibenzyl(n-methyl)amine hybrids: potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease. J. Med. Chem. 2014; 57, 3773-3785. Go to original source... Go to PubMed...
    33. Di Pietro O., Viayna E., Vicente-García E., Bartolini M., Ramón R., Juárez-Jiménez J., Clos M. V., Pérez B., Andrisano V., Luque F. J., Lavilla R., Muñoz-Torrero D. 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies. Eur. J. Med. Chem. 2014; 73, 141-152. Go to original source... Go to PubMed...
    34. Wang J., Wang Z.-M., Li X.-M., Li F., Wu J.-J., Kong L.-Y., Wang X.-B. Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer's disease based on the fusion of donepezil and melatonin. Bioorg. Med. Chem. 2016; 24, 4324-4338. Go to original source... Go to PubMed...
    35. Zhu J. T. T., Choi R. C. Y., Chu G. K. Y., Cheung A. W. H., Gao Q. T., Li J., Jiang Z. Y., Dong T. T. X., Tsim K. W. K. Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: A comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J. Agric. Food Chem. 2007; 55, 2438-2445. Go to original source... Go to PubMed...
    36. Verghese J. Isolation of curcumin from Curcuma Longa L. Rhizome. Flavour Fragr. J. 1993; 8, 315-319. Go to original source...
    37. Katsuyama Y., Kita T., Funa N., Horinouchi S. Curcuminoid biosynthesis by two type III polyketide synthases in the herb Curcuma Longa. J. Biol. Chem. 2009; 284, 11160-11170. Go to original source... Go to PubMed...
    38. Ammon H. P., Wahl M. A. Pharmacology of Curcuma Longa. Planta Med. 1991; 57, 1-7. Go to original source... Go to PubMed...
    39. Dairam A., Fogel R., Daya S., Limson J. L. Antioxidant and iron-binding properties of curcumin, capsaicin, and s-allylcysteine reduce oxidative stress in rat brain homogenate. J. Agric. Food Chem. 2008; 56, 3350-3356. Go to original source... Go to PubMed...
    40. Park S.-Y., Kim D. S. H. L. Discovery of natural products from Curcuma Longa that protect cells from beta-amyloid insult: A drug discovery effort against Alzheimer's disease. J. Nat. Prod. 2002; 65, 1227-1231. Go to original source... Go to PubMed...
    41. Kim H., Park B.-S., Lee K.-G., Choi C. Y., Jang S. S., Kim Y.-H., Lee S.-E. Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J. Agric. Food Chem. 2005; 53, 8537-8541. Go to original source... Go to PubMed...
    42. Shimmyo Y., Kihara T., Akaike A., Niidome T., Sugimoto H. Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. Neuroreport 2008; 19, 1329-1333. Go to original source... Go to PubMed...
    43. Derosa G., Maffioli P., Simental-Mendía L. E., Bo S., Sahebkar A. Effect of curcumin on circulating interleukin-6 concentrations: A systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. 2016; 111, 394-404. Go to original source... Go to PubMed...
    44. Tang M., Taghibiglou C. The mechanisms of action of curcumin in Alzheimer's disease. J. Alzheimers Dis. JAD 2017; 58, 1003-1016. Go to original source... Go to PubMed...
    45. Chojnacki J. E., Liu K., Yan X., Toldo S., Selden T., Estrada M., Rodríguez-Franco M. I., Halquist M. S., Ye D., Zhang S. Discovery of 5-(4-Hydroxyphenyl)-3-Oxo-Pentanoic Acid [2-(5-Methoxy-1H-Indol-3-Yl)-Ethyl]-Amide as a neuroprotectant for Alzheimer's disease by hybridization of curcumin and melatonin. ACS Chem. Neurosci. 2014; 5, 690-699. Go to original source... Go to PubMed...
    46. Gerenu G., Liu K., Chojnacki J. E., Saathoff J. M., Martínez-Martín P., Perry G., Zhu X., Lee H.-G., Zhang S. Curcumin/melatonin hybrid 5-(4-Hydroxy-Phenyl)-3-Oxo-Pentanoic Acid [2-(5-Methoxy-1H-Indol-3-Yl)-Ethyl]-Amide ameliorates AD-like pathology in the APP/PS1 mouse model. ACS Chem. Neurosci. 2015; 6, 1393-1399. Go to original source... Go to PubMed...
    47. Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 2013; 53, 401-426. Go to original source... Go to PubMed...
    48. Buendia I., Navarro E., Michalska P., Gameiro I., Egea J., Abril S., López A., González-Lafuente L., López M. G., León R. New Melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection. Future Med. Chem. 2015; 7, 1961-1969. Go to original source... Go to PubMed...
    49. Pähkla R., Zilmer M., Kullisaar T., Rägo L. Comparison of the antioxidant activity of melatonin and pinoline in vitro. J. Pineal Res. 1998; 24, 96-101. Go to original source... Go to PubMed...
    50. Susilo R., Rommelspacher H. Formation of 1-methyl-beta-carbolines in rats from their possible carboxylic acid precursor. Naunyn. Schmiedebergs Arch. Pharmacol. 1988; 337, 566-571. Go to original source... Go to PubMed...
    51. de la Fuente Revenga M., Pérez C., Morales-García J. A., Alonso-Gil S., Pérez-Castillo A., Caignard D.-H., Yáñez M., Gamo A. M., Rodríguez-Franco M. I. Neurogenic potential assessment and pharmacological characterization of 6-Methoxy-1,2,3,4-Tetrahydro-β-Carboline (Pinoline) and melatonin-pinoline hybrids. ACS Chem. Neurosci. 2015; 6, 800-810. Go to original source... Go to PubMed...
    52. Mason R. P., Olmstead E. G., Jacob R. F. Antioxidant activity of the monoamine oxidase B inhibitor lazabemide. Biochem. Pharmacol. 2000; 60, 709-716. Go to original source... Go to PubMed...
    53. Fiedorowicz J. G., Swartz K. L. The role of monoamine oxidase inhibitors in current psychiatric practice. J. Psychiatr. Pract. 2004; 10, 239-248. Go to original source... Go to PubMed...
    54. Xie Q., Wang H., Xia Z., Lu M., Zhang W., Wang X., Fu W., Tang Y., Sheng W., Li W., Zhou W., Zhu X., Qiu Z., Chen H. Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-β aggregation. J. Med. Chem. 2008; 51, 2027-2036. Go to original source... Go to PubMed...
    55. Cheng S., Zheng W., Gong P., Zhou Q., Xie Q., Yu L., Zhang P., Chen L., Li J., Chen J., Chen H., Chen H. (-)-meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy. Bioorg. Med. Chem. 2015; 23, 3110-3118. Go to original source... Go to PubMed...
    56. Benchekroun M., Romero A., Egea J., León R., Michalska P., Buendía I., Jimeno M. L., Jun D., Janockova J., Sepsova V., Soukup O., Bautista-Aguilera O. M., Refouvelet B., Ouari O., Marco-Contelles J., Ismaili L. The antioxidant additive approach for Alzheimer's disease therapy: new ferulic (lipoic) acid plus melatonin modified tacrines as cholinesterases inhibitors, direct antioxidants, and nuclear factor (erythroid-derived 2)-like 2 activators. J. Med. Chem. 2016; 59, 9967-9973. Go to original source... Go to PubMed...
    57. Soukup O., Jun D., Zdarova-Karasova J., Patocka J., Musilek K., Korabecny J., Krusek J., Kaniakova M., Sepsova V., Mandikova J., Trejtnar F., Pohanka M., Drtinova L., Pavlik M., Tobin G., Kuca K. A Resurrection of 7-MEOTA: A comparison with tacrine. Curr. Alzheimer Res. 2013; 10, 893-906. Go to original source... Go to PubMed...
    58. Maresova P., Klimova B., Novotny M., Kuca K. Alzheimer's and Parkinson's diseases: expected economic impact on Europe-a call for a uniform european strategy. J. Alzheimers Dis. JAD 2016; 54, 1123-1133. Go to original source... Go to PubMed...

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