Abstract:
:The finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ) and promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multifunctional AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. To this end, we have developed a new class of selective AChE inhibitors with site-activated chelating activity. The identified lead, HLA20A, exhibits little affinity for metal (Fe, Cu, and Zn) ions but can be activated following inhibition of AChE to liberate an active chelator, HLA20. HLA20 has been shown to possess neuroprotective and neurorescuing activities in vitro and in vivo with the ability to lower amyloid precursor holoprotein (APP) expression and Aβ generation and inhibit Aβ aggregation induced by metal (Fe, Cu, and Zn) ion. HLA20A inhibited AChE in a time and concentration dependent manner with an HLA20A-AChE complex constant (K(i)) of 9.66 × 10(-6) M, a carbamylation rate (k(+2)) of 0.14 min(-1), and a second-order rate (k(i)) of 1.45 × 10 (4) M(-1) min(-1), comparable to those of rivastigmine. HLA20A showed little iron-binding capacity and activity against iron-induced lipid peroxidation (LPO) at concentrations of 1-50 μM, while HLA20 exhibited high potency in iron-binding and in inhibiting iron-induced LPO. At a concentration of 10 μM, HLA20A showed some activity against monoamine oxidase (MAO)-A and -B when tested in rat brain homogenates. Defined restrictively by Lipinski's rules, both HLA20A and HLA20 satisfied drug-like criteria and possible oral and brain permeability, but HLA20A was more lipophilic and considerably less toxic in human SHSY5Y neuroblastoma cells at high concentrations (25 or 50 μM). Together our data suggest that HLA20A may represent a promising lead for further development for Alzheimer's disease therapy.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Zheng H,Youdim MB,Fridkin Mdoi
10.1021/cn100069csubject
Has Abstractpub_date
2010-11-17 00:00:00pages
737-46issue
11issn
1948-7193journal_volume
1pub_type
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journal_title:ACS chemical neuroscience
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journal_title:ACS chemical neuroscience
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journal_title:ACS chemical neuroscience
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更新日期:2015-09-16 00:00:00
abstract::In our efforts to develop hybrid compounds of curcumin and melatonin as potential disease-modifying agents for Alzheimer's disease (AD), a potent lead hybrid compound, Z-CM-I-1, has been recently identified and biologically characterized in vitro. In this work, we report the in vivo effects of Z-CM-I-1 on AD pathologi...
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abstract::The nitrocatechol derivatives tolcapone (1) and entacapone (2), used as adjunctive therapy in the treatment of Parkinson's disease, were investigated for their potential to inhibit the tau-derived-hexapeptide 306VQIVYK311. They were compared to small molecules that contain similar pharmacophores including the catechol...
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journal_title:ACS chemical neuroscience
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更新日期:2020-03-18 00:00:00
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journal_title:ACS chemical neuroscience
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00519
更新日期:2021-01-27 00:00:00
abstract::Recent clinical approvals of brain imaging radiotracers targeting amyloid-β provided clinicians the tools to detect and confirm Alzheimer's disease pathology without autopsy or biopsy. While current imaging agents are effective in postsymptomatic Alzheimer's patients, there is much room for improvement in earlier diag...
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doi:10.1021/acschemneuro.9b00093
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00250
更新日期:2018-12-19 00:00:00
abstract::Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Aβ and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer's disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00350
更新日期:2018-03-21 00:00:00
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journal_title:ACS chemical neuroscience
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doi:10.1021/acschemneuro.0c00024
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
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更新日期:2014-08-20 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
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更新日期:2013-08-21 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn300003r
更新日期:2012-07-18 00:00:00
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journal_title:ACS chemical neuroscience
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更新日期:2014-03-19 00:00:00
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journal_title:ACS chemical neuroscience
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
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更新日期:2019-03-20 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
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更新日期:2019-07-17 00:00:00
abstract::On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven...
journal_title:ACS chemical neuroscience
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更新日期:2018-07-18 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
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更新日期:2011-11-16 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
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更新日期:2019-10-16 00:00:00
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journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00074
更新日期:2015-08-19 00:00:00
abstract::The development of a noninvasive method for the detection of Alzheimer's disease is of high current interest, which can be critical in early diagnosis and in guiding treatment of the disease. The aggregates of β-amyloid are a pathological hallmark of Alzheimer's disease. Carbohydrates such as gangliosides have been sh...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn3002015
更新日期:2013-04-17 00:00:00
abstract::Temozolomide (TMZ) is the current first-line chemotherapy for treatment of glioblastoma multiforme (GBM). However, similar to other brain therapeutic compounds, access of TMZ to brain tumors is impaired by the blood-brain barrier (BBB) leading to poor response for GBM patients. To overcome this major hurdle, we have s...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00339
更新日期:2018-12-19 00:00:00