Can molecular similarity-activity models for intravenous general anaesthetics help explain their mechanism of action?

The importance of molecular shape and electrostatic potential in determining the activities of 11 structurally-diverse i.v. general anaesthetics was investigated using computational chemistry techniques.

The free plasma anaesthetic concentrations that abolished the response to noxious stimulation were obtained from the literature. The similarities in the molecular shapes and electrostatic potentials of the agents to eltanolone (the most potent anaesthetic agent in the group) were calculated using Carbo indices, and correlated with in vivo potency.

The best model obtained was based on the similarities of the anaesthetics to two eltanolone conformers (r2=0.820). This model correctly predicted the potencies of the R- and S-enantiomers of ketamine, but identified alphaxalone as an outlier. Exclusion of alphaxalone substantially improved the activity correlation (r2=0.972). A bench mark model based on octanol/water partition coefficients (r2=0.647) failed to predict the potency order of the ketamine enantiomers.

The results demonstrate that a single activity model can be formulated for chiral and non-chiral i.v. anaesthetic agents using molecular similarity indices.