What makes a molecule an anaesthetic What makes a molecule an anaesthetic? Studies on the mechanisms of anaesthesia using a physicochemical approach  J.W. Sear  British Journal of Anaesthesia  Volume 103, Issue 1, Pages 50-60 (July 2009) DOI: 10.1093/bja/aep092 Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 1 Correlation between observed anaesthetic potencies and values predicted using (a) olive oil/gas partition coefficients and (b) the shape similarity model for a series of ethers. It can be seen that not only does the shape similarity model improve the potency predictions of the conventional anaesthetics, but it also accurately predicts the activities of the transitional agents and the potency order for the enantiomers of isoflurane—two areas where the non-polar solubility model fails. (Reproduced, with permission from the editor and publishers, from reference 63.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 2 Correlation between observed anaesthetic potencies and values predicted using the CoMFA model for the training and test set compounds. The numbers refer to the individual anaesthetic agents as listed below, and the diagonal represents the correlation that would be obtained with a perfect model. The CoMFA model explained 94.0% of the variance in the observed activities of the training set agents (P<0.0001), and was a good predictor of activity for the test set compounds (r2=0.799). Note that the model correctly predicts that the S(+) stereoisomer of ketamine (compound 4) is more potent than the R(−) stereoisomer (compound 9). 1, Eltanolone; 2, minaxolone; 3, ORG 21465; 4, methohexital; 5, thiamylal; 6, thiopental; 7, R(+) etomidate; 8, ORG 25435; 9, R(−) ketamine; 10, clomethiazole; 11, alphaxalone; 12, pentobarbital; 13, propofol; 14, S(+) ketamine. (Reproduced with permission from reference 66.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 3 Electrostatic pharmacophoric map. (a) Spatial distribution of regions where negative (red, standard deviation×coefficient less than −0.002) and positive (blue, standard deviation×coefficient greater than +0.001) potential are favoured for high anaesthetic potency. The arrows in (b) and (c) show the regions where eltanolone and thiopental, respectively, qualitatively fit this map. Note that the lower potency thiopental fits at fewer points compared with eltanolone, the lead structure and most potent anaesthetic in the group. (Reproduced with permission from reference 66.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 4 Steric pharmacophoric map. (a) Spatial distribution of regions where molecular bulk is favoured (green, standard deviation×coefficient greater than +0.0018) and disfavoured (purple, standard deviation×coefficient less than −0.0008) for high anaesthetic potency. The orientation of this map is the same as the electrostatic equivalent. By rotating about the x-axis by 85° (b), it can be seen that the two areas where molecular bulk is disfavoured (I and J) are located above and below the plane of the steroid ring of eltanolone. (Reproduced with permission from reference 66.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 5 Correlation between observed anaesthetic potencies and values predicted using non-polar solubilities (Log P) for the training and test set compounds. The model explained 78.3% of the variance in the observed activities of the training set agents (P=0.0007), but had poor predictive capability for the test set compounds (r2=0.272). Note that the non-polar solubility is also unable to predict the different potencies of S(+) and R(−) stereoisomers of the chiral anaesthetic ketamine (compounds 14 and 9, respectively). Agent notation as in Figure 2. (Reproduced with permission from reference 66.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 6 (a) and (b) Preliminary electrostatic and steric CoMFA maps for immobilizing activity and 20% depression of mean arterial pressure for 8 i.v. anaesthetic agents (the lead agent, as shown in the figures, is eltanolone). British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 7 (a) Electrostatic pharmacophoric map for the halogenated volatile anaesthetics, showing the spatial arrangements of the key regions where positive (blue; K, L) and negative (red; M, N) electrostatic potential are favoured. Note that the view of negative-favoured region N is obscured. (b) Steric map for the halogenated anaesthetics, showing the regions where molecular bulk is favoured (green; O, P, Q) or disfavoured (purple; R, S) for high anaesthetic potency. (c) Orientation of the most potent anaesthetic in the group CF2H-(CH2)3-CH2OH with respect to the electrostatic map. Arrows indicate regions where the electrostatic potential of the molecule qualitatively fits the template. Crosses indicate areas where there is a discrepancy. Substitution of electropositive hydrogen atoms in these regions may lead to increased anaesthetic activity. (d) Orientation of hexafluorobenzene with respect to the steric map. The bulk disfavoured regions R and S lie in front and behind the plane of the aromatic ring. (e) Electrostatic and (f) steric pharmacophoric maps for non-halogenated volatile anaesthetics. These maps have been orientated to fit the three centres (F–J–I) (highlighted in red) to Q–R–S on the halogenated anaesthetic map. Combined (g) electrostatic and (h) steric maps for both halogenated and non-halogenated volatile anaesthetics based on the three centre fit. Superimposing the maps indicates that the key electrostatic and steric regions are spatially compatible. Note all isocontour thresholds are based on a 40% individual negative or positive contribution to the activity model. (Reproduced, with permission from the editor and publishers, from reference 69.) British Journal of Anaesthesia 2009 103, 50-60DOI: (10.1093/bja/aep092) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions