PMID: 9428657Jan 15, 1998Paper

Long chain analogs of physostigmine as potential drugs for Alzheimer's disease: new insights into the mechanism of action in the inhibition of acetylcholinesterase

Biochimica Et Biophysica Acta
E PerolaM Brufani

Abstract

Heptylphysostigmine is in advanced clinical trial as a drug for Alzheimer's disease. 8-Morpholinooctylphysostigmine and 8-(cis-2,6-dimethylmorpholino)octylphysostigmine are currently undergoing pre-clinical evaluation. The mechanism of action of these compounds in the inhibition of acetylcholinesterase has been investigated. All the examined compounds display non competitive-like kinetics of inhibition. There are no reversible components in the observed inhibition: the whole inhibitory effect is due to the time-dependent pseudo-irreversible carbamylation of the active site. Yet the observed time course of the inhibition does not match a simple second order kinetics. An influence of the quaternary structure of the enzyme on the more complex kinetics of carbamylation is hypothesized. Reactivation experiments on the inhibited enzyme show long lasting inhibitory effects for these compounds. The higher duration of the anticholinesterase effect of the morpholino derivatives compared to heptylphysostigmine should provide the basis for their higher therapeutic potential.

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Citations

Dec 13, 2005·Journal of Molecular Modeling·Laleh Alisaraie, Gregor Fels
Nov 20, 2012·Biochemistry. Biokhimii︠a︡·P Masson
Feb 14, 2016·Archives of Biochemistry and Biophysics·Patrick Masson, Sofya V Lushchekina
Jul 29, 2000·Drug Development and Industrial Pharmacy·J L ChenC H Chiang
Oct 28, 2008·Journal of Chromatography. a·Manuela BartoliniVincenza Andrisano
Jul 9, 2010·Drug Metabolism and Pharmacokinetics·Yoshihiko ItoShizuo Yamada
Mar 10, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Qiong XieZhuibai Qiu
Dec 17, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Marco PistolozziWen Tan
Oct 3, 2017·Biological & Pharmaceutical Bulletin·Keisuke ObaraYoshio Tanaka
Mar 2, 2019·Current Alzheimer Research·Eva MezeiovaJan Korabecny
Jun 19, 2002·CNS Drug Reviews·Luigia TrabaceVincenzo Cuomo
Feb 2, 2021·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Keisuke Obara, Yoshio Tanaka
Jun 9, 2019·Chemico-biological Interactions·Terrone L Rosenberry, Jonah Cheung
Jul 28, 2020·Neuropharmacology·Sofya V Lushchekina, Patrick Masson
Jul 11, 2018·Journal of Medicinal Chemistry·Sonali S BharateRam A Vishwakarma
Mar 8, 2012·ACS Medicinal Chemistry Letters·Angela RampaVincenzo Di Marzo

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