(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics

J Med Chem. 1991 Jan;34(1):397-403. doi: 10.1021/jm00105a061.


This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.

Publication types

  • Comparative Study

MeSH terms

  • Analgesics / chemical synthesis*
  • Animals
  • Brain / metabolism
  • Guinea Pigs
  • Indicators and Reagents
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, kappa
  • Structure-Activity Relationship


  • Analgesics
  • Indicators and Reagents
  • Piperidines
  • Receptors, Opioid
  • Receptors, Opioid, kappa