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Molecular Pharmacology

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Research ArticleArticle

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Efrat Groner, Yacov Ashani, Donna Schorer-Apelbaum, Jeffrey Sterling, Yaacov Herzig and Marta Weinstock
Molecular Pharmacology June 2007, 71 (6) 1610-1617; DOI: https://doi.org/10.1124/mol.107.033928
Efrat Groner
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Yacov Ashani
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Donna Schorer-Apelbaum
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Jeffrey Sterling
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Yaacov Herzig
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Marta Weinstock
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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 (ki) and decarbamylation (kr) 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. ki was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that ki 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.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.033928.

  • ABBREVIATIONS: AChE, acetylcholinesterase; ACh, acetylcholine; BChE, butyrylcholinesterase; TcAChE, AChE of Torpedo californica; AD, Alzheimer's disease; ChE, cholinesterase; MAO, monoamine oxidase; rhAChE, recombinant human acetylcholinesterase; hBChE, human butyrylcholinesterase; ATC, acetylthiocholine; BTC, butyrylthiocholine iodide; AI, aminoindan; PE, phenylethylamine.

    • Received January 9, 2007.
    • Accepted March 8, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Efrat Groner, Yacov Ashani, Donna Schorer-Apelbaum, Jeffrey Sterling, Yaacov Herzig and Marta Weinstock
Molecular Pharmacology June 1, 2007, 71 (6) 1610-1617; DOI: https://doi.org/10.1124/mol.107.033928

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Research ArticleArticle

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Efrat Groner, Yacov Ashani, Donna Schorer-Apelbaum, Jeffrey Sterling, Yaacov Herzig and Marta Weinstock
Molecular Pharmacology June 1, 2007, 71 (6) 1610-1617; DOI: https://doi.org/10.1124/mol.107.033928
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