title: Development of pharmacophoric maps for cardiovascular depression by intravenous anaesthetic agents: comparison with maps for immobilizing activity.
abstract: BACKGROUND
  The molecular basis of the cardiovascular effects of i.v. anaesthetics was investigated using comparative molecular field analysis (CoMFA).
  
  
  METHODS
  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 EC(50) plasma concentrations, and by determination of plasma-free drug concentrations associated with a 20% decrease in MAP (dMAP(20)). Data were obtained both from the literature and from unpublished data of the author.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.
  
  
  RESULTS
  The final model for cardiovascular depression based on free drug concentrations associated with dMAP(20) explained 95.8% of the variance in observed activities, with a cross-validated q(2) of 0.824 (n=12). A second model based on change in MAP at EC(50) plasma concentrations explained 98.3% of the variance in arterial pressure, but performed poorly at cross-validation (q(2) 0.526). The comparative model for immobilizing potency had an r(2) value of 0.987 and q(2) 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. john.sear@nda.ox.ac.uk
authors.forename: J W
authors.initials: JW
authors.lastname: Sear
mesh_terms: D018686:Anesthetics, Intravenous / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003198:Computer Simulation; D003864:Depression, Chemical; D006801:Humans; D008958:Models, Molecular; D009068:Movement / Q000187:drug effects; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D018686:Anesthetics, Intravenous