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From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer’s Disease

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NeuroPsychopharmacotherapy

Abstract

Alzheimer’s disease (AD) is a multifactorial syndrome involving a complex array of different, while related factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel multimodal compounds, as follows: the brain selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity, M30; the chelating with neuroprotective activity, HLA20; the acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity, HLA20A; the AChE-MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity, M30D; and neuroprotective peptide NAPVSIPQ analogs. Among them, HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency, AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including the major role of oxidative stress (OS) due to accumulation of iron in AD brains and formation of free oxygen radicals, modulation of amyloid-β (Aβ) and amyloid precursor protein expression/processing and tau, induction of cell cycle arrest; inhibition of neuronal death markers, upregulation of neurotrophic factors, as well as activation of protein kinase C and mitogen-activated protein kinase signaling pathways.

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Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Intra-cellular Therapies Inc., New York, NY, USA

    Hailin Zheng

  2. Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases and Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine, Haifa, Israel

    Tamar Amit, Orit Bar-Am, Silvia A. Mandel & Moussa B. H. Youdim

  3. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel

    Mati Fridkin

  4. Department of Biology, Yonsei World Central University, Seoul, South Korea

    Moussa B. H. Youdim

Authors
  1. Hailin Zheng
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  2. Tamar Amit
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  3. Orit Bar-Am
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  4. Mati Fridkin
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  5. Silvia A. Mandel
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  6. Moussa B. H. Youdim
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Corresponding authors

Correspondence to Hailin Zheng or Silvia A. Mandel .

Editor information

Editors and Affiliations

  1. Dept Psychiatry , Psychosomatics & Psychotherapy, University of Würzburg, Medical School Clinical Neurochemistry, Würzburg, Germany

    Peter Riederer

  2. Inst für Psychologische Medizin, Haag, Bayern, Germany

    Gerd Laux

  3. Department of Psychiatry, University of Toronto Department of Psychiatry, Toronto, ON, Canada

    Benoit Mulsant

  4. Center Translational Res Neurol Diseases, Dalian Med Uni Shanghai Inst Health Sc Center Translational Res Neurol Diseases, Dalian, China

    Weidong Le

  5. Fujita Health University School Medicine, Toyoake, Aichi, Japan

    Toshiharu Nagatsu

Section Editor information

  1. Fujita Health University School of Medicine, Toyoake, Aichi, Japan

    Toshiharu Nagatsu

  2. Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan

    Toshiharu Nagatsu

  3. Department of Physiological Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

    Akira Nakashima

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Zheng, H., Amit, T., Bar-Am, O., Fridkin, M., Mandel, S.A., Youdim, M.B.H. (2020). From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer’s Disease. In: Riederer, P., Laux, G., Mulsant, B., Le, W., Nagatsu, T. (eds) NeuroPsychopharmacotherapy. Springer, Cham. https://doi.org/10.1007/978-3-319-56015-1_234-1

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  • DOI: https://doi.org/10.1007/978-3-319-56015-1_234-1

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