Received for publication January 9, 2007.
Revised March 8, 2007.
Accepted for publication March 8, 2007.

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 to rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k_i) and decarbamylation (k_r) of recombinant human acetylcholinesterase (rhAChE) 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 butyrylcholinesterase (hBChE) 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.

Key words: Structure-activity relationships and modeling, Carboxylesterase