title: Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogues.
abstract: The synthesis of a series of 1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole 5-alkylcarbamates and their resolution are reported. These compounds are structurally related to physostigmine with substitution of a methylene group in place of the NMe group at position 8 of physostigmine. Many of these 8-carbaphysostigmine analogues are more potent acetylcholinesterase inhibitors in vitro and less toxic in vivo than physostigmine. The (-)-enantiomer (e.g., 1d and 1g) possessing the same absolute configuration at C3a and C8a as that of physostigmine, is about 6 to 12-fold more potent at inhibiting acetylcholinesterase than the corresponding (+)-enantiomer (e.g., 1e and 1h).
authors.affiliation: Medicinal Chemistry Department, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Hedberg
authors.forename: A
authors.initials: A
authors.lastname: Dunaiskis
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Russo
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: J
authors.initials: J
authors.lastname: Ives
authors.forename: D
authors.initials: D
authors.lastname: Liston
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010830:Physostigmine