Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase

Sultan Darvesh, Katherine V. Darvesh, Robert S. McDonald, Diane Mataija, Ryan Walsh, Sam Mothana, Oksana Lockridge, Earl Martin

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to π-π interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the π-cationic site of the Ω-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.

Original languageEnglish (US)
Pages (from-to)4200-4212
Number of pages13
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
DOIs
StatePublished - Jul 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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