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

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.

• Authors: Qian-Sheng Yu, Harold W Holloway, Weiming Luo, Debomoy K Lahiri, Arnold Brossi, Nigel H Greig
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 13 Pg. 4687-93 (Jul 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20627738 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Cholinesterase Inhibitors
• Phenylcarbamates
• Neostigmine
• Physostigmine
• Acetylcholinesterase
• Butyrylcholinesterase
• Pyridostigmine Bromide

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Animals
• Butyrylcholinesterase (chemistry, metabolism)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, therapeutic use)
• Humans
• Mice
• Myasthenia Gravis (drug therapy)
• Neostigmine (chemistry)
• Phenylcarbamates (chemical synthesis, chemistry, therapeutic use)
• Physostigmine (chemistry)
• Pyridostigmine Bromide (chemistry)