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.
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.
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Qian-Sheng
QS
Yu
Marcella
M
Reale
Mohammad A
MA
Kamal
Harold W
HW
Holloway
Weiming
W
Luo
Kumar
K
Sambamurti
Balmiki
B
Ray
Debomoy K
DK
Lahiri
Jack T
JT
Rogers
Nigel H
NH
Greig
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013237:Stereoisomerism; D051844:alpha-Synuclein / Q000096:biosynthesis
D016564:Amyloid beta-Protein Precursor; D053583:Interleukin-1beta; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D051844:alpha-Synuclein; D010830:Physostigmine; C092280:phenserine