Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders
Abstract
:1. Introduction
2. Multifactorial Diseases
Neurodegenerative Disorders
3. Multifunctional Drugs
- Both palliative and disease modifying actions;
- Additive or synergistic therapeutic responses;
- Reduced risk of drug-drug interactions;
- Improved drug characteristics (for example ADME properties);
- More predictable pharmacokinetics and pharmacodynamic relationships;
- Prolonged duration of effectiveness;
- Simplified therapeutic regimen;
- Lower costs.
4. Oxidative Stress
5. Chemical Antioxidants
- Primary antioxidants (Type I, chain breaking or free radical scavengers): directly react with free radicals yielding less reactive species that are unable to damage biological targets, or end the radical chain reaction.
- Secondary antioxidants (Type II, or preventive): exert their protection by chemical routes that do not involve direct reactions with free radicals, such as metal chelation, absorption of UV radiation, deactivation of singlet oxygen, repair of primary antioxidants, and decomposition of hydroperoxide into nonradical species.
- Tertiary antioxidants (Type III, or fixers): capable of repairing, mainly through H or electron transfer, biomolecules that are oxidatively damaged and restore their pristine structures.
- Multifunctional antioxidants (Type IV, or versatile): can combine more than one of the above-mentioned means of action, or one of them with enhancing enzymatic protection or restoring pathways in the endogenous antioxidative defense system.
6. Melatonin
- Melatonin has very low toxicity [103].
7. Derivatives
7.1. From Nature
7.2. From the Lab
7.3. Computational Designed
- (i)
- Building the candidates;
- (ii)
- Sampling the search space;
- (iii)
- Evaluating their potential for the desired purpose.
- Free radical scavenging capability;
- Metal chelation properties (OH inactivating ligand behavior);
- Low toxicity;
- Adequate permeation and bioavailability;
- Non-difficult manufacturability;
- No pro-oxidant behavior;
- Efficient for repairing oxidatively damaged biological targets;
- Inhibition of COMT, AChE and/or MAO.
8. Summary
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AChE | acetylcholinesterase |
AD | Alzheimer’s disease |
ADME | absorption, distribution, metabolism, and excretion |
ALS | amyotrophic lateral sclerosis |
AOC | antioxidant capacity |
BBB | brain blood barrier |
CNN | central nervous system |
CADMA-Chem | Computer-assisted Design of Multifunctional Antioxidants, based on chemical properties |
COMT | catechol-O-methyltransferase |
HD | Huntington’s disease |
MAO | monoamine oxidase |
MD | multifactorial diseases |
MFD | multifunctional drugs |
NDD | neurodegenerative disorders |
OS | oxidative stress |
PD | Parkinson’s disease |
RNS | reactive oxnitrogen species |
ROS | reactive oxygen species |
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Actions | Ref. | |
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AFMK | Hydroxyl radical scavenger. Radiation protector. Inhibitor of lipid peroxidation and OS-induced neuronal damage. Inhibitor of OS induced by Cu(II)-ascorbate mixtures. ROS scavenger. RNS scavenger. Protector against diverse oxidants. | [177,178,179] [180] [177,178,179,181] [113] [182,183,184] [185,186,187,188,189] [183,190,191] |
Serotonin | Inhibitor of lipid peroxidation. ROS scavenger. Fe(II) chelator. Inhibitor of •OH production. | [123] [121] [192] [125] |
NAS | Neuroprotector. Antioxidant and anti-aging protector. Inhibitor of DNA oxidation induced by H2O2 and Cr(III). Inhibitor of UV-induced cataracts. Inhibitor of Cu-induced lipoproteins oxidation. Inhibitor of lipid peroxidation. Keeper of optimal fluidity of the biological membranes. | [193,194] [195] [196,197,198] [44] [199,200] [201,202,203,204] [205] |
6OHM | Inhibitor of quinolinic-acid induced neurotoxicity. Inhibitor of UV-induced OS. Inhibitor of KCN-induced O2•− production. Inhibitor of iron-induced lipid peroxidation. Inhibitor of cyanide-induced OS. Inhibitor of thiobarbituric acid-induced lipid peroxidation. | [206] [183] [207] [208,209] [207] [210] |
c3OHM | Scavenger of ABTS•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation). | [211] |
Peroxyl radicals scavenger. | [212] | |
Hydroxyl radical scavenger. | [173,212] | |
Inhibitor of OS induced by Cu(II)-ascorbate mixtures. | [113] | |
5HTP | Anti-inflammatory. Free radical scavenger. Inhibitor of iron-induced lipid peroxidation. Inhibitor of Fe/ascorbate-induced oxidation. Metal chelator. Inhibitor of UV-induced apoptosis in human monocytes. | [114] [115] [116] [117] [120] [119] |
5MTA | Hydroxyl radical scavenger. Inhibitor of lipid peroxidation. Hypochlorous acid deactivator. Inhibitor of malondialdehyde formation. Inhibitor of exercise-induced cellular oxidative changes | [212] [213,214] [201] [215] [216] |
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Galano, A.; Guzmán-López, E.G.; Reiter, R.J. Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders. Int. J. Mol. Sci. 2021, 22, 11584. https://doi.org/10.3390/ijms222111584
Galano A, Guzmán-López EG, Reiter RJ. Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders. International Journal of Molecular Sciences. 2021; 22(21):11584. https://doi.org/10.3390/ijms222111584
Chicago/Turabian StyleGalano, Annia, Eduardo G. Guzmán-López, and Russel J. Reiter. 2021. "Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders" International Journal of Molecular Sciences 22, no. 21: 11584. https://doi.org/10.3390/ijms222111584