title: 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.affiliation: Drug Design & Development Section, Laboratory of Neurosciences, Biomedical Research Center, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Weiming
authors.initials: W
authors.lastname: Luo
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009157:Myasthenia Gravis / Q000188:drug therapy*; D009388:Neostigmine / Q000737:chemistry*; D048448:Phenylcarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D010830:Physostigmine / Q000737:chemistry*; D011729:Pyridostigmine Bromide / Q000737:chemistry*
chemical_list: D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D009388:Neostigmine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D011729:Pyridostigmine Bromide