ArticleAnti-inflammatory & anti-allergy agents in medicinal chemistry2013
Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-Synuclein synthesis, interleukin-1β release, and cholinergic action.
Article in Anti-inflammatory & anti-allergy agents in medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 26 citations in OpenAlex.
- Pharmacokinetics of Novel Crystalline Buntanetap in Mice, Dogs, and Humans.Biomolecules · 2025Article
- Neuroprotective Strategies and Cell-Based Biomarkers for Manganese-Induced Toxicity in Human Neuroblastoma (SH-SY5Y) Cells.Biomolecules · 2024Article
- The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Article
- Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression.Pharmaceutics · 2021Article
- Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis.International journal of molecular sciences · 2021Review
- Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers.International journal of molecular sciences · 2020Review
- Iron-responsive-like elements and neurodegenerative ferroptosis.Learning & memory (Cold Spring Harbor, N.Y.) · 2020Review
- Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain.iScience · 2020Article
- Novel approaches to counter protein aggregation pathology in Parkinson's disease.Progress in brain research · 2020Review
- Alzheimer's Disease and Its Potential Alternative Therapeutics.Journal of Alzheimer's disease & Parkinsonism · 2019Article
- Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice.American journal of neurodegenerative disease · 2019Article
- Iron in Neurodegeneration - Cause or Consequence?Frontiers in neuroscience · 2019Review
- Nitric Oxide, Iron and Neurodegeneration.Frontiers in neuroscience · 2019Review
- Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse.Alzheimer's & dementia (New York, N. Y.) · 2018Article
- Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases.Molecular neurodegeneration · 2017Review
- Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine.Journal of biomedical science · 2017Review
- αν and β1 Integrins mediate Aβ-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.PloS one · 2014Article
- (-)-Phenserine attenuates soman-induced neuropathology.PloS one · 2014Article
- Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease.PloS one · 2013Article
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Authors and funding
10 authors at 7 institutions in 3 countries.
Funding
Abstract
A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβ levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.
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