Development of pharmacophoric maps for cardiovascular depression by intravenous anaesthetic agents: comparison with maps for immobilizing activity

• Published in: British journal of anaesthesia : BJA Vol. 104; no. 6; pp. 684 - 690
• Main Author: Sear, J.W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-06-2010; Oxford University Press
• Subjects: anaesthetics i.v; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Intravenous - blood; Anesthetics, Intravenous - chemistry; Anesthetics, Intravenous - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; cardiovascular depression; comparative molecular field analysis; Computer Simulation; Depression, Chemical; Humans; indices of potency; Medical sciences; model, computer simulation; Models, Molecular; Movement - drug effects; Static Electricity; Structure-Activity Relationship; cardiovascular depression; indices of potency; anaesthetics i.v; model, computer simulation; comparative molecular field analysis; Mood disorder; Intravenous administration; Computer simulation; Anesthesia; Depression; Simulation model; Comparative study
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aeq100

The molecular basis of the cardiovascular effects of i.v. anaesthetics was investigated using comparative molecular field analysis (CoMFA).
The cardiovascular effects, measured as changes in mean arterial pressure (MAP), compared with awake values of continuous infusions of 13 structurally diverse i.v. anaesthetics were compared at EC50 plasma concentrations, and by determination of plasma-free drug concentrations associated with a 20% decrease in MAP (dMAP20). Data were obtained both from the literature and from unpublished data of the author. The results were fitted to a CoMFA activity model using field-fit minimization techniques to maximize similarities in molecular bulk and electrostatic potential to the lead compound, eltanolone.
The final model for cardiovascular depression based on free drug concentrations associated with dMAP20 explained 95.8% of the variance in observed activities, with a cross-validated q2 of 0.824 (n=12). A second model based on change in MAP at EC50 plasma concentrations explained 98.3% of the variance in arterial pressure, but performed poorly at cross-validation (q2 0.526). The comparative model for immobilizing potency had an r2 value of 0.987 and q2 0.823. Comparison of pharmacophoric maps showed several key electrostatic and steric regions common to both models when isocontours were constructed linking lattice grid points, making the greatest 40% contributions (87.57% for electrostatic fields and 86.16% for steric fields).
Comparison of activity models for cardiovascular depression and immobilizing potency for i.v. anaesthetics shows significant commonality, suggesting that it may not be possible to separate those molecular features associated with each of these effects.