Design, synthesis and biological evaluation of novel procaine derivatives for intravenous anesthesia

Bioorg Med Chem Lett. 2022 Mar 15:60:128587. doi: 10.1016/j.bmcl.2022.128587. Epub 2022 Jan 26.

Abstract

A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f, 6g, 6h, 6o, 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among whichcompound 6h (TI = 2.68)was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 μM.

Keywords: Continuous infusion; NMDA receptor; Procaine; Safety evaluation; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia, Intravenous
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Procaine / administration & dosage
  • Procaine / chemistry
  • Procaine / pharmacology*
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Procaine