title: Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine.
abstract: An explosion in the incidence of neurodegenerative diseases, particularly Alzheimer's disease (AD), is predicted in coming decades. Hence, the need to devise and assess new treatment strategies has never been more acute. AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy: primarily with acetylcholinesterase (AChE) inhibitors to amplify remaining cholinergic activity. New agents that, additionally, affect disease progression are sorely needed. Inhibition of brain butyrylcholinesterase (BuChE) represents a new drug target for AD treatment. Therefore, hand-in-hand with the development of selective ligands to inhibit BuChE in brain, it is fundamental to optimize assay conditions for kinetic studies of human BuChE. Kinetic analysis of serum BuChE, which is structurally similar to brain enzyme, was performed at dual substrate (butyrylthiocholine iodide) concentration ranges: 3-80 microM (low) and 25-800 microM (optimal) by use of the Ellman technique. Interaction of BuChE with a novel experimental AD therapeutic, bisnorcymserine (BNC; 0.06-2.0 nM) was also studied ex vivo. The IC_{50} and other key kinetic constants were determined for human serum BuChE inhibition by BNC, which proved to be a highly potent inhibitor in comparison to its structural analogue, cymserine. BNC may, additionally, lower the amyloid plaque-associated protein, amyloid-beta peptide. In synopsis, the characterization of the kinetic parameters of BuChE and BNC, described herein, is both aiding in the design of novel agents and optimizing their translation toward clinical use.
authors.affiliation: Enzymoics, 7 Peterlee Pl., Hebersham, NSW 2770, Australia.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
authors.forename: Peter
authors.initials: P
authors.lastname: Klein
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D010830:Physostigmine; D002091:Butyrylcholinesterase; C517198:bisnorcymserine; C092280:phenserine