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.
Keywords: Acetylcholinesterase, Alzheimer disease, amyloid-β peptide (Aβ), amyloid-β precursor protein (APP), Posiphen,
(+)-N1-norPosiphen, (+)-N8-norPosiphen, (+)-N1, N8-bisnorPosiphen, (-)-phenserine, α-synuclein, interleukin-1β, muscarinic
receptor, nicotinic receptor, butyrylcholinesterase, Parkinson’s disease.
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