Oxford Meeting - November 2002

What physico-chemical properties of i.v. drugs confer hypnosis and other effects?

 J.C. Sewell and J.W. Sear

Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU.

The molecular mechanisms by which intravenous general anaesthetics induce anaesthesia have not been established. Recent studies of mechanisms have been predominantly target-orientated; investigating the activities of general anaesthetics at putative sites of action, such as the GABA_A receptors [1,2]. An alternative approach to studying mechanisms is to focus on the anaesthetic molecules themselves. The aim of such-ligand orientated approaches is to identify the physico- chemical molecular properties that determine activity, and to formulate an activity model that correlates the magnitude of these properties with anesthetic potency. Previous physico-chemical models for intravenous general anaesthetics have generally been restricted to structurally homologous series of agents (such as analogues of propofol [3,4]), with few effective models being derived for structurally heterologous series.

We have investigated whether physico-chemical activity models can be formulated for structurally diverse i.v. anaesthetics using molecular modelling techniques. A group of 14 chemically diverse agents were considered. The free plasma concentrations (-log EC50) that abolish movement to a noxious stimulus were obtained from the literature. The anaesthetics were divided into a training set of 9 compounds (eltanolone, minaxolone, Org 21465, pentobarbital, thiopental, methohexital, R-ketamine, propofol, chlormethiazole) used to formulate the activity model; and a test set of 5 agents (alphaxalone, thiamylal, Org 25435, S-ketamine and R-etomidate) used to evaluate the model's predictability.

Activity models were derived using a combination of molecular similarity [5] and comparative molecular field analysis techniques [6], that correlate in vivo anaesthetic potency with the spatial distribution of molecular bulk and electrostatic potential. The final model explained 92.8% of the variance in the observed activities of the training set compounds (n=9, P < 0.001). The model accurately predicted the potencies of 3 of the 5 test set agents: Org 25435 predicted log EC50 = 5.44 (observed log EC50 = 5.42), thiamylal 4.59 (4.81) and S-ketamine 5.28 (5.37). However, the model was less effective at predicting the activities of R-etomidate 5.08 (5.99) and alphaxalone 6.69 (5.06).

The results demonstrate that a single activity model with good predictability can be formulated for chemically diverse i. v. general anaesthetics. Furthennore, the mapping of the spatial arrangement of the key electrostatic and steric features contributing to the model enabled the derivation of a preliminary three-dimensional 'pharmacophore' for i.v. anaesthetic activity, which could be developed for the rational design of novel anaesthetic agents.

This work was supported by a project grant from the British Journal of Anaesthesia.

1. Belelli D et al. The interaction of general anaesthetics and neurosteroids with GABA_A and Glycine receptors. Neurochern Int. 1999; 34: 447-452.
2. Krasowski MD & Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999; 55: 1278-1303.
3. Trapani et al. Propofol in Anesthesia. Mechanism of action, structure-activity relationships and drug delivery. Current Med Chern. 2000; 7: 249-271.
4. Krasowski et at. 4D-QSAR Analysis of a set of propofo1 analogues: Mapping binding sites for an anesthetic phenol on the GABA_A receptor. J Med Chern. 2002; 45: 3210-3221.
5. Sewell JC & Sear JW. Can molecular similarity-activity models for intravenous general anaesthetics help explain their mechanism of action? BrJ Anaesth. 2002; 88: 166-174.
6. Sewell JC & Sear JW. A preliminary CoMF A model for chemically diverse intravenous general anaesthetics. Br J Anaesth. 2002; 89: 672P-673P.