Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease?

SY Han, JE Sweeney, ES Bachman, EJ Schweiger, G. Forloni, JT Coyle, BM Davis, MM Joullié

Research output: Contribution to journalArticle

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Abstract

We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent. One derivative, galanthamine n-butyl carbamate, had an LD50 of over 100 mg/kg (ip) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose. With this surprisingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.

Original languageEnglish
Pages (from-to)673-687
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume27
Issue number7
DOIs
Publication statusPublished - 1992

Fingerprint

Galantamine
Cholinesterase Inhibitors
Alzheimer Disease
Pharmacology
Derivatives
Molecular modeling
Carbamates
Lethal Dose 50
Neurology
Bioactivity
Hydroxyl Radical
Cholinergic Agents
Conformations
Central Nervous System
Therapeutics

Keywords

  • acetylcholinesterase inhibitor
  • Alzheimer's disease
  • basal forebrain lesion
  • galanthamine derivatives
  • molecular modeling
  • passive avoidance

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease? / Han, SY; Sweeney, JE; Bachman, ES; Schweiger, EJ; Forloni, G.; Coyle, JT; Davis, BM; Joullié, MM.

In: European Journal of Medicinal Chemistry, Vol. 27, No. 7, 1992, p. 673-687.

Research output: Contribution to journalArticle

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AU - Coyle, JT

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AU - Joullié, MM

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