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Iron In Alzheimer's
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ironjustice
Mar 6, 2012, 9:54:02 AM3/6/12
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Parkinson's Drug Rasagiline to Novel Multitarget Iron Chelators with
Acetylcholinesterase and Monoamine Oxidase Inhibitory and
Neuroprotective Properties for Alzheimer's Disease
Journal of Alzheimer's Disease
Hailin Zheng1, Tamar Amit2, Orit Bar-Am2, Mati Fridkin3, Moussa B.H.
Youdim2, 4, Silvia A. Mandel2
1Department of Medicinal Chemistry, Intra-Cellular Therapies Inc., New
York, NY, USA
2Eve Topf and USA National Parkinson Foundation Centers of Excellence
for Neurodegenerative Diseases and Department of Pharmacology,
Technion-Rappaport Family Faculty of Medicine Haifa, Haifa, Israel
3Department of Organic Chemistry, The Weizmann Institute of Science,
Rehovot, Israel
4Department of Biology, Yonsei World Central University, Seoul, South
Korea
Subject Group Medicine and Health
Online Date Friday, March 02, 2012
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 hybrid molecules with
multimodal activity, including:
i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B
inhibitor with chelating and neuroprotective activity;
ii) HLA20, a brain permeable metal chelator with neuroprotective
activity;
iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-
activated chelating and neuroprotective activity; iv) M30D, an AChE
and MAO-A and -B inhibitor with site-activated chelating and
neuroprotective activity; and
v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. 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 and 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 modulation of amyloid-
β and amyloid-β protein precursor expression/processing; induction of
cell cycle arrest; inhibition of neuronal death markers; and
upregulation of neurotrophic factors, as well as activation of protein
kinase signaling pathways.
Publisher IOS Press
ISSN 1387-2877 (Print)
1875-8908 (Online)
Subject Medicine, Clinical Neurology and Internal Medicine
DOI 10.3233/JAD-2012-120013
Copyright ©2012 IOS Press All rights reserved.
Acetylcholinesterase and Monoamine Oxidase Inhibitory and
Neuroprotective Properties for Alzheimer's Disease
Journal of Alzheimer's Disease
Hailin Zheng1, Tamar Amit2, Orit Bar-Am2, Mati Fridkin3, Moussa B.H.
Youdim2, 4, Silvia A. Mandel2
1Department of Medicinal Chemistry, Intra-Cellular Therapies Inc., New
York, NY, USA
2Eve Topf and USA National Parkinson Foundation Centers of Excellence
for Neurodegenerative Diseases and Department of Pharmacology,
Technion-Rappaport Family Faculty of Medicine Haifa, Haifa, Israel
3Department of Organic Chemistry, The Weizmann Institute of Science,
Rehovot, Israel
4Department of Biology, Yonsei World Central University, Seoul, South
Korea
Subject Group Medicine and Health
Online Date Friday, March 02, 2012
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 hybrid molecules with
multimodal activity, including:
i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B
inhibitor with chelating and neuroprotective activity;
ii) HLA20, a brain permeable metal chelator with neuroprotective
activity;
iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-
activated chelating and neuroprotective activity; iv) M30D, an AChE
and MAO-A and -B inhibitor with site-activated chelating and
neuroprotective activity; and
v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. 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 and 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 modulation of amyloid-
β and amyloid-β protein precursor expression/processing; induction of
cell cycle arrest; inhibition of neuronal death markers; and
upregulation of neurotrophic factors, as well as activation of protein
kinase signaling pathways.
Publisher IOS Press
ISSN 1387-2877 (Print)
1875-8908 (Online)
Subject Medicine, Clinical Neurology and Internal Medicine
DOI 10.3233/JAD-2012-120013
Copyright ©2012 IOS Press All rights reserved.
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