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

Qian sheng Yu, Marcella Reale, Mohammad A. Kamal, Harold W. Holloway, Weiming Luo, Kumar Sambamurti, Balmiki Ray, Debomoy Lahiri, Jack T. Rogers, Nigel H. Greig

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)117-128
Number of pages12
JournalAnti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry
Volume12
Issue number2
DOIs
StatePublished - 2013

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Synucleins
Amyloid beta-Protein Precursor
Interleukin-1
Cholinergic Agents
Pharmaceutical Preparations
Alzheimer Disease
Clinical Trials
Macrophage Colony-Stimulating Factor
phenserine
Inhibition (Psychology)
Cholinesterases
Amyloid Plaques
Nicotinic Receptors
Muscarinic Receptors
Amyloid
Blood Cells
Cytokines
Inflammation

Keywords

  • α-synuclein
  • (+)-N
  • (+)-N-norPosiphen
  • (+)-N-norPosiphen
  • (-)-phenserine
  • Acetylcholinesterase
  • Alzheimer disease
  • Amyloid-β peptide (Aβ)
  • Amyloid-β precursor protein (APP)
  • Butyrylcholinesterase
  • Interleukin-1β
  • Muscarinic receptor
  • N-bisnorPosiphen
  • Nicotinic receptor
  • Parkinson's disease
  • Posiphen

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pharmacology

Cite this

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. / Yu, Qian sheng; Reale, Marcella; Kamal, Mohammad A.; Holloway, Harold W.; Luo, Weiming; Sambamurti, Kumar; Ray, Balmiki; Lahiri, Debomoy; Rogers, Jack T.; Greig, Nigel H.

In: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, Vol. 12, No. 2, 2013, p. 117-128.

Research output: Contribution to journalArticle

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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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AU - Yu, Qian sheng

AU - Reale, Marcella

AU - Kamal, Mohammad A.

AU - Holloway, Harold W.

AU - Luo, Weiming

AU - Sambamurti, Kumar

AU - Ray, Balmiki

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AU - Greig, Nigel H.

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AB - 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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