title: The kinetics of inhibition of human acetylcholinesterase and butyrylcholinesterase by two series of novel carbamates.
abstract: Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k(i)) and decarbamylation (k(r)) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k(i) was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k(i) depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.
authors.affiliation: Department of Pharmacology, Hebrew University, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Groner
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ashani
authors.forename: Donna
authors.initials: D
authors.lastname: Schorer-Apelbaum
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sterling
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Herzig
authors.forename: Marta
authors.initials: M
authors.lastname: Weinstock
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D002091:Butyrylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D007266:Inhibition, Psychological; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology / Q000627:therapeutic use; D000068836:Rivastigmine; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002219:Carbamates; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D048448:Phenylcarbamates; C031967:rasagiline; D012642:Selegiline; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000068836:Rivastigmine