Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents

• Published in: British journal of anaesthesia : BJA Vol. 106; no. 3; pp. 312 - 318
• Main Author: Sear, J. W.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-03-2011
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Intravenous - administration & dosage; Anesthetics, Intravenous - chemistry; Anesthetics, Intravenous - pharmacology; Biological and medical sciences; Chemistry, Physical; Computer Simulation; Humans; Infusions, Intravenous; Injections, Intravenous; Medical sciences; Models, Molecular; Quantitative Structure-Activity Relationship; Static Electricity; indices of potency; anaesthetics i.v; model, computer simulation; comparative molecular field analysis; Intravenous administration; Computer simulation; Anesthesia; model
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aeq376

Background
The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA).
Methods
ED50 induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC50 plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone.
Results
The final CoMFA model for the ED50 induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q2=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r2=0.988 and q2=0.852. Although there was a correlation between –log ED50 and –log EC50 (r2=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1).
Conclusions
Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.