Long-acting anticholinesterases for myasthenia gravis: Synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine

Qian Sheng Yu, Harold W. Holloway, Weiming Luo, Debomoy K. Lahiri, Arnold Brossi, Nigel H. Greig

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.

Original languageEnglish (US)
Pages (from-to)4687-4693
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number13
DOIs
StatePublished - Jun 2 2010

Keywords

  • (-)-Cymserine
  • (-)-Phenserine
  • Congenital myasthenic syndromes
  • Myasthenia gravis
  • N-Phenylcarbamate analogues of (-)-physostigmine
  • Neostigmine
  • Pyridostigmine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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