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Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
Address correspondence to John W. Sear, PhD, FFARCS, Nuffield Department of Anesthetics, University of Oxford, The John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Address e-mail to john.sear{at}nda.ox.ac.uk Reprints will not be available from the authors.
We investigated the molecular basis for the immobilizing activity of nonhalogenated volatile anesthetics by using comparative molecular field analysis (CoMFA). In vivo potency data (expressed as minimum alveolar anesthetic concentrations) for 38 structurally diverse drugs were obtained from the literature. The anesthetics were randomly divided into a training-set (n = 28) used to formulate the activity models and a test-set (n = 10) used to independently assess the models’ predictive power. The anesthetic structures were aligned to maximize their similarity in molecular shape and electrostatic potential to conformers of the most active drug in the group: hexanol. The individual conformers and alignments with maximum similarity (calculated with combined Carbo indices) were retained and used to derive the CoMFA activity models. The final CoMFA model explained 95.5% of the variance in the observed activities of the training-set anesthetics. The model had good predictive capability for both the training-set drugs (cross-validated r2 = 0.824) and the randomly excluded test-set anesthetics (r2 = 0.921). Pharmacophoric maps were derived by identifying the spatial distribution of key areas in which steric and electrostatic interactions are important in determining the immobilizing activity of the anesthetics considered.
IMPLICATIONS: We have derived an activity model for a group of structurally diverse nonhalogenated volatile anesthetics that correlates in vivo potency (minimum alveolar anesthetic concentration) with the spatial distribution of their molecular bulk and electrostatic potential. Our results suggest that there is a common molecular basis for the immobilizing activity of the anesthetics.
This article has been cited by other articles:
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  J. W. Sear What makes a molecule an anaesthetic? Studies on the mechanisms of anaesthesia using a physicochemical approach Br. J. Anaesth., July 1, 2009; 103(1): 50 - 60. [Abstract] [Full Text] [PDF]
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 J. C. Sewell, D. E. Raines, E. I. Eger II, M. J. Laster, and J. W. Sear A Comparison of the Molecular Bases for N-Methyl-d-Aspartate-Receptor Inhibition Versus Immobilizing Activities of Volatile Aromatic Anesthetics Anesth. Analg., January 1, 2009; 108(1): 168 - 175. [Abstract] [Full Text] [PDF]
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E. I. Eger II, D. E. Raines, S. L. Shafer, H. C. Hemmings Jr, and J. M. Sonner Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? Anesth. Analg., September 1, 2008; 107(3): 832 - 848. [Abstract] [Full Text] [PDF]
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J. M. Sonner A Hypothesis on the Origin and Evolution of the Response to Inhaled Anesthetics Anesth. Analg., September 1, 2008; 107(3): 849 - 854. [Abstract] [Full Text] [PDF]
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J. G. Bovill Anesthetic Pharmacology: Reflections of a Section Editor Anesth. Analg., November 1, 2007; 105(5): 1186 - 1190. [Full Text] [PDF]
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J. C. Sewell and J. W. Sear Determinants of volatile general anesthetic potency: a preliminary three-dimensional pharmacophore for halogenated anesthetics. Anesth. Analg., March 1, 2006; 102(3): 764 - 771. [Abstract] [Full Text] [PDF]
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