Syntheses, Resolution, and Structure-Activity Relationships of Potent Acetylcholinesterase Inhibitors: 8-carbaphysostigmine Analogues

J Med Chem. 1992 Apr 17;35(8):1429-34. doi: 10.1021/jm00086a011.

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).

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Cholinesterase Inhibitors / chemical synthesis*
  • Lethal Dose 50
  • Male
  • Mice
  • Physostigmine / analogs & derivatives*
  • Physostigmine / chemistry
  • Physostigmine / toxicity
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Physostigmine