ChemInform Abstract: The Chemistry of Dementia.

Iversen, Sara Mosberg

doi:10.1002/chin.198838338

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“…The relationship between peptide transmitters and modulators, peptidomimetic agents and the incorporation of the x,y-dinucleophile functionality into molecules should be added to the armamentarium of the medicinal chemist, particularly in terms of their interaction with the receptor structure. Quoting a recent provocative article by Susan Iversen: "The possibility of developing selective cholinergic agonists and antagonists for the different receptors in different tissues and areas of the brain opens a new era of cholinergic pharmacology" [43].…”

Section: Resultsmentioning

confidence: 99%

Medicinal agents incorporating the 1,2-diamine functionality

Michalson

Szmuszkovicz

1989

Progress in Drug Research

124

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Section: Resultsmentioning

confidence: 99%

Medicinal agents incorporating the 1,2-diamine functionality

Michalson

Szmuszkovicz

1989

Progress in Drug Research

124

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Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Sugimoto¹,

Iimura²,

Yamanishi³

et al. 1995

J. Med. Chem.

311

177

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Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).

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ChemInform Abstract: The Chemistry of Dementia.

Cited by 2 publications

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Medicinal agents incorporating the 1,2-diamine functionality

Medicinal agents incorporating the 1,2-diamine functionality

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

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