Yu_2013_Antiinflamm.Antiallergy.Agents.Med.Chem_12_117

Reference

Title : 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, alpha -Synuclein Synthesis, Interleukin-1beta Release, and Cholinergic Action - Yu_2013_Antiinflamm.Antiallergy.Agents.Med.Chem_12_117
Author(s) : Yu QS , Reale M , Kamal MA , Holloway HW , Luo W , Sambamurti K , Ray B , Lahiri DK , Rogers JT , Greig NH
Ref : Antiinflamm Antiallergy Agents Med Chem , 12 :117 , 2013
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 beta-amyloid peptide (Abeta) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Abeta 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,alpha-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and alpha-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)-1beta release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.

PubMedSearch : Yu_2013_Antiinflamm.Antiallergy.Agents.Med.Chem_12_117
PubMedID: 23360256

Related information

Inhibitor Posiphen

Citations formats

Yu QS, Reale M, Kamal MA, Holloway HW, Luo W, Sambamurti K, Ray B, Lahiri DK, Rogers JT, Greig NH (2013)
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, alpha -Synuclein Synthesis, Interleukin-1beta Release, and Cholinergic Action
Antiinflamm Antiallergy Agents Med Chem 12 :117

Yu QS, Reale M, Kamal MA, Holloway HW, Luo W, Sambamurti K, Ray B, Lahiri DK, Rogers JT, Greig NH (2013)
Antiinflamm Antiallergy Agents Med Chem 12 :117