Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain

Bioorg Med Chem. 2019 Apr 1;27(7):1226-1231. doi: 10.1016/j.bmc.2019.02.010. Epub 2019 Feb 5.

Abstract

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine's psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic linker chain. More stable amide and ethylsulfone analogues generally showed weaker anaesthetic/analgesic activity. There was no correlation between the anaesthetic/analgesic properties of the compounds and their binding affinities for the N-methyl-d-aspartate (NMDA) receptor.

Keywords: Anaesthesia; Esters; Ketamine; Short-acting; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / administration & dosage
  • Amides / pharmacology*
  • Anesthetics / administration & dosage
  • Anesthetics / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Esters / administration & dosage
  • Esters / pharmacology*
  • Female
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Molecular Structure
  • Nociception / drug effects*
  • Pain Measurement
  • Pain Threshold / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Anesthetics
  • Esters
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine