4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor

J Med Chem. 2002 Jul 18;45(15):3210-21. doi: 10.1021/jm010461a.


A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the gamma-aminobutyric acid type A (GABA(A)) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand-receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand -OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABA(A) receptor; it follows that the GABA(A) receptor is therefore the likely site of propofol's anesthetic action.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Anesthetics, General / chemistry*
  • Anesthetics, General / pharmacology
  • Animals
  • Binding Sites
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Larva
  • Ligands
  • Models, Molecular
  • Propofol / analogs & derivatives*
  • Propofol / chemistry*
  • Propofol / pharmacology
  • Protein Subunits
  • Quantitative Structure-Activity Relationship
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / drug effects
  • Structure-Activity Relationship
  • Xenopus laevis / physiology


  • Anesthetics, General
  • Excitatory Amino Acid Agonists
  • Ligands
  • Protein Subunits
  • Receptors, GABA-A
  • Propofol