Abstract
BackgroundIsoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold) than R-isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1) with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies.MethodsFirst, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA) displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay.ResultsBoth enantiomers decreased 1-AMA fluorescence signal (at 520 nm), indicating that both competed with 1-AMA and bound to the αL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 “lovastatin site.” ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay.ConclusionsIn contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R-isoflurane.
Highlights
Many biologically active molecules, including drugs, exist in different chiral forms, and it is possible that each specific enantiomer can interact with their targets differently, thereby potentially eliciting different biological responses
The interaction of 1-AMA with leukocyte function-associated antigen-1 (LFA-1) 1-AMA is a small molecule with environment-dependent fluorescence and general anesthetic properties as demonstrated by the potentiation of gamma-aminobutyric acid (GABA)-ergic transmission [24,25,26]
We explored the size of available cavities on the surface of aL I domain and found that only the ‘‘lovastatin site’’ was a larger cavity than 1-AMA
Summary
Many biologically active molecules, including drugs, exist in different chiral forms, and it is possible that each specific enantiomer can interact with their targets differently, thereby potentially eliciting different biological responses. The potential exists for a racemic mixture of a compound to cause diverse, and perhaps unwanted, side effects. Regardless, racemic drugs are used commonly in clinical medicine, as the purification or synthesis of one specific enantiomer can be costly. While the majority of drugs on the market were sold as racemic mixtures in early 1990s, about 40% of drugs were marketed as single enantiomers by 2002 [1]. The advantages of using specific enantiomers over the racemic mixture might include their less complex and more selective pharmacodynamic profiles, and the potential for improved therapeutic index and the reduction of side effects. We have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies
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