2-(3,4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- Ethyl]-Acetamides: The Use of Conformational Analysis in the Development of a Novel Series of Potent Opioid Kappa Agonists

J Med Chem. 1991 Jan;34(1):181-9. doi: 10.1021/jm00105a027.

Abstract

This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa agonist N-[2-(1-pyrrolidinyl)cyclohexyl] acetamide U-50488 might possess kappa agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.

Publication types

  • Comparative Study

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / pharmacology
  • Analgesia*
  • Analgesics / chemical synthesis*
  • Animals
  • Female
  • Guinea Pigs
  • In Vitro Techniques
  • Indicators and Reagents
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Conformation
  • Molecular Structure
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Naloxone / metabolism
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, mu
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology
  • X-Ray Diffraction

Substances

  • Acetamides
  • Analgesics
  • Indicators and Reagents
  • Pyrrolidines
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • Naloxone