Professor Ishikawa asks an interesting question: If dipole–dipole interactions explain the selectivity for sites that underlie potency differences between the structural isomers isoflurane and enflurane,1how does one explain the potency difference between two compounds with no difference in dipole moment, e.g. , the enantiomers of isoflurane?2The question, however, implies that differences in potency are always produced via  occupancy of different binding sites, rather than different occupancy of common sites. It is important to recognize that either case can produce differences in potency. For the structural  isomers, we found the different physiochemical nature of similar-sized molecules (isoflurane and enflurane) was sufficient to actually select for different sites on albumin.1As might be predicted from site selectivity, the clinical differences between these drugs extend beyond that of just potency. Inhaled anesthetic enantiomers , however, are, as Dr. Ishikawa points out, identical physicochemically. We would therefore argue that their small differences in potency are due to differing occupancy of common sites. A recent crystallographic study supports this contention.3In cocrystallized complexes of apoferritin and the racemic mixture of halothane (1:1), there was a 2:1 occupancy preference of the S  over the R  enantiomer in a common binding site. The differences in occupancy result from even weaker interactions than the dipole–dipole ones. For example, subtle differences in the distance of specific halogens from polar atoms on residues such as serine and tyrosine predict slightly improved interactions for S  as compared with R  halothane. Relevant data for the isoflurane enantiomers do not yet exist, although we see no reason for them to be different. Certainly, there is a complete absence of evidence that enantiomers of such small molecules can select for unique protein sites.

We agree however, with Professor Ishikawa’s final sentence regarding the complexity of features underlying anesthetic binding sites. Dipole moment is only one feature, but like molecular volume and surface area, it is a fairly strong one—enough to provide for site selectivity, a form of coarse tuning. Within a given site, there are a host of weaker features: steric, electrostatic, and thermodynamic, which combine to provide the fine tuning—the modulation of occupancy. The combination of unique sites and varying occupancy of those sites gives each of our inhaled anesthetics its unique clinical flavor.

*University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Liu R, Eckenhoff RG: Weak polar interactions confer albumin binding site selectivity for the haloether anesthetics. Anesthesiology 2005; 102:799–805
Lysko GS, Robinson JL, Casto R, Ferrone RA: The stereospecific effects of isoflurane isomers in vivo. Eur J Pharmacol 1994; 263:25–9
Liu R, Loll PJ, Eckenhoff RG: Structural basis for high affinity volatile anesthetic binding in a natural 4-helix bundle protein. FASEB J 2005; 19:567–76