Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives

J Med Chem. 1992 Nov 27;35(24):4542-8. doi: 10.1021/jm00102a005.

Abstract

Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.

Publication types

  • Comparative Study

MeSH terms

  • Acetylcholinesterase
  • Animals
  • Brain / enzymology
  • Butyrylcholinesterase
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology*
  • Male
  • Molecular Structure
  • Phthalimides / chemical synthesis*
  • Phthalimides / pharmacology*
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Phthalimides
  • Piperidines
  • 1-benzyl-4-(2-(4-(benzoylamino)phthalimido)ethyl)piperidine
  • Acetylcholinesterase
  • Butyrylcholinesterase