J C Sewell1, J W Sear. 1. Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
Abstract
BACKGROUND: The molecular basis of i.v. general anaesthetic activity was investigated using comparative molecular field analysis (CoMFA). METHODS: The free plasma concentrations that abolish movement to a noxious stimulus for 14 structurally diverse i.v. anaesthetics were obtained from the literature. The compounds were randomly divided into a training set (n=10) to derive the activity model, and a separate test set (n=4) used to assess its predictive capability. The anaesthetic structures were aligned so as to maximize their similarities in molecular shape and electrostatic potential to conformers of the most active agent in the group, eltanolone. The conformers and alignments that showed the maximum similarity (calculated using combined Carbo indices) were retained, and used to derive the CoMFA models. RESULTS: The final model explained 94.0% of the variance in the observed activities of the training set (n=10, P<0.0001) and was a good predictor of test set activity (n=4, r(2)=0.799). In contrast, a model based on non-polar solubility (LogP) explained only 78.3% of the variance in the observed activities of the training set (n=10, P=0.0007) and was a poor predictor for the test set (n=4, r(2)=0.272). Further analysis of the CoMFA results identified the spatial distribution of key areas where steric and electrostatic interactions are important in determining the activity of the 14 anaesthetics considered. CONCLUSIONS: A single activity model can be formulated for i.v. general anaesthetics and preliminary pharmacophoric maps derived, which describe the molecular basis of their in vivo potency.
BACKGROUND: The molecular basis of i.v. general anaesthetic activity was investigated using comparative molecular field analysis (CoMFA). METHODS: The free plasma concentrations that abolish movement to a noxious stimulus for 14 structurally diverse i.v. anaesthetics were obtained from the literature. The compounds were randomly divided into a training set (n=10) to derive the activity model, and a separate test set (n=4) used to assess its predictive capability. The anaesthetic structures were aligned so as to maximize their similarities in molecular shape and electrostatic potential to conformers of the most active agent in the group, eltanolone. The conformers and alignments that showed the maximum similarity (calculated using combined Carbo indices) were retained, and used to derive the CoMFA models. RESULTS: The final model explained 94.0% of the variance in the observed activities of the training set (n=10, P<0.0001) and was a good predictor of test set activity (n=4, r(2)=0.799). In contrast, a model based on non-polar solubility (LogP) explained only 78.3% of the variance in the observed activities of the training set (n=10, P=0.0007) and was a poor predictor for the test set (n=4, r(2)=0.272). Further analysis of the CoMFA results identified the spatial distribution of key areas where steric and electrostatic interactions are important in determining the activity of the 14 anaesthetics considered. CONCLUSIONS: A single activity model can be formulated for i.v. general anaesthetics and preliminary pharmacophoric maps derived, which describe the molecular basis of their in vivo potency.
Authors: Ervin Pejo; Peter Santer; Lei Wang; Philip Dershwitz; S Shaukat Husain; Douglas E Raines Journal: Anesthesiology Date: 2016-03 Impact factor: 7.892
Authors: L Sangeetha Vedula; Grace Brannigan; Nicoleta J Economou; Jin Xi; Michael A Hall; Renyu Liu; Matthew J Rossi; William P Dailey; Kimberly C Grasty; Michael L Klein; Roderic G Eckenhoff; Patrick J Loll Journal: J Biol Chem Date: 2009-07-15 Impact factor: 5.157