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ANESTHETIC PHARMACOLOGY

Determinants of Volatile General Anesthetic Potency: A Preliminary Three-Dimensional Pharmacophore for Halogenated Anesthetics

Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK

Address correspondence to John W. Sear, PhD, FFARCS, Nuffield Department of Anaesthetics, University of Oxford, The John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Address e-mail to john.sear{at}nda.ox.ac.uk.

We investigated the molecular basis for the immobilizing activity of halogenated volatile anesthetics using comparative molecular field analysis. In vivo potency data (expressed as minimum alveolar concentrations) for 69 structurally diverse anesthetics were obtained from the literature. The drugs were randomly divided into a training set (n = 52) used to derive the activity model and a test set (n = 17) used to independently assess the model's predictive power. The anesthetic structures were aligned so as to maximize their similarity in molecular shape and electrostatic potential to the most potent drug in the group, CF₂H-(CF₂)₃-CH₂OH. The conformers and alignments of the anesthetics with maximum similarity (calculated as Carbo indices) were retained and used to derive the comparative molecular field analysis models. The final model explained 94.2% of the variance in the observed activities of the training set compounds. The model showed good predictive capability for both the training set (cross-validated r² = 0.705) and randomly excluded test set anesthetics (r² = 0.837). Three-dimensional pharmacophoric maps were derived to identify the spatial distribution of key areas where steric and electrostatic interactions are important in determining immobilizing activity of the halogenated drugs and were compared with our previously published maps obtained for nonhalogenated volatile anesthetics.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999