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. 2001 May;80(5):2284–2297. doi: 10.1016/S0006-3495(01)76200-5

Breaking the Meyer-Overton rule: predicted effects of varying stiffness and interfacial activity on the intrinsic potency of anesthetics.

R S Cantor 1
PMCID: PMC1301419  PMID: 11325730

Abstract

Exceptions to the Meyer-Overton rule are commonly cited as evidence against indirect, membrane-mediated mechanisms of general anesthesia. However, another interpretation is possible within the context of an indirect mechanism in which solubilization of an anesthetic in the membrane causes a redistribution of lateral pressures in the membrane, which in turn shifts the conformational equilibrium of membrane proteins such as ligand-gated ion channels. It is suggested that compounds of different stiffness and interfacial activity have different intrinsic potencies, i.e., they cause widely different redistributions of the pressure profile (and thus different effects on protein conformational equilibria) per unit concentration of the compound in the membrane. Calculations incorporating the greater stiffness of perfluoromethylenic chains and the large interfacial attraction of hydroxyl groups predict the higher intrinsic potency of short alkanols than alkanes, the cutoffs in potency of alkanes and alkanols and the much shorter cutoffs for their perfluorinated analogues. Both effects, increased stiffness and interfacial activity, are present in unsaturated hydrocarbon solutes, and the intrinsic potencies are predicted to depend on the magnitude of both effects and on the number and locations of multiple bonds within the molecule. Most importantly, the intrinsic potencies of polymeric alkanols with regularly spaced hydroxyl groups are predicted to rise with increasing chain length, without cutoff; such molecules should serve to distinguish unambiguously between indirect mechanisms and direct binding mechanisms of anesthesia.

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Selected References

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  1. Cantor R. S. Lipid composition and the lateral pressure profile in bilayers. Biophys J. 1999 May;76(5):2625–2639. doi: 10.1016/S0006-3495(99)77415-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cantor R. S. Solute modulation of conformational equilibria in intrinsic membrane proteins: apparent "cooperativity" without binding. Biophys J. 1999 Nov;77(5):2643–2647. doi: 10.1016/S0006-3495(99)77098-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cantor R. S. The influence of membrane lateral pressures on simple geometric models of protein conformational equilibria. Chem Phys Lipids. 1999 Aug;101(1):45–56. doi: 10.1016/s0009-3084(99)00054-7. [DOI] [PubMed] [Google Scholar]
  4. Cantor R. S. The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Toxicol Lett. 1998 Nov 23;100-101:451–458. doi: 10.1016/s0378-4274(98)00220-3. [DOI] [PubMed] [Google Scholar]
  5. Chipot C., Wilson M. A., Pohorille A. Interactions of anesthetics with the water-hexane interface. A molecular dynamics study. J Phys Chem B. 1997 Jan 30;101(5):782–791. doi: 10.1021/jp961513o. [DOI] [PubMed] [Google Scholar]
  6. Eckenhoff R. G., Johansson J. S. Molecular interactions between inhaled anesthetics and proteins. Pharmacol Rev. 1997 Dec;49(4):343–367. [PubMed] [Google Scholar]
  7. Eger E. I., 2nd, Halsey M. J., Harris R. A., Koblin D. D., Pohorille A., Sewell J. C., Sonner J. M., Trudell J. R. Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart. Anesth Analg. 1999 Jun;88(6):1395–1400. doi: 10.1097/00000539-199906000-00036. [DOI] [PubMed] [Google Scholar]
  8. Eger E. I., 2nd, Ionescu P., Laster M. J., Gong D., Hudlicky T., Kendig J. J., Harris R. A., Trudell J. R., Pohorille A. Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis. Anesth Analg. 1999 Apr;88(4):867–876. doi: 10.1097/00000539-199904000-00035. [DOI] [PubMed] [Google Scholar]
  9. Eger E. I., 2nd, Liu J., Koblin D. D., Laster M. J., Taheri S., Halsey M. J., Ionescu P., Chortkoff B. S., Hudlicky T. Molecular properties of the "ideal" inhaled anesthetic: studies of fluorinated methanes, ethanes, propanes, and butanes. Anesth Analg. 1994 Aug;79(2):245–251. doi: 10.1213/00000539-199408000-00007. [DOI] [PubMed] [Google Scholar]
  10. Fang Z., Ionescu P., Chortkoff B. S., Kandel L., Sonner J., Laster M. J., Eger E. I., 2nd Anesthetic potencies of n-alkanols: results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics. Anesth Analg. 1997 May;84(5):1042–1048. doi: 10.1097/00000539-199705000-00017. [DOI] [PubMed] [Google Scholar]
  11. Franks N. P., Lieb W. R. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994 Feb 17;367(6464):607–614. doi: 10.1038/367607a0. [DOI] [PubMed] [Google Scholar]
  12. Franks N. P., Lieb W. R. Molecular mechanisms of general anaesthesia. Nature. 1982 Dec 9;300(5892):487–493. doi: 10.1038/300487a0. [DOI] [PubMed] [Google Scholar]
  13. Franks N. P., Lieb W. R. Partitioning of long-chain alcohols into lipid bilayers: implications for mechanisms of general anesthesia. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5116–5120. doi: 10.1073/pnas.83.14.5116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Franks N. P., Lieb W. R. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science. 1991 Oct 18;254(5030):427–430. doi: 10.1126/science.1925602. [DOI] [PubMed] [Google Scholar]
  15. Franks N. P., Lieb W. R. Where do general anaesthetics act? Nature. 1978 Jul 27;274(5669):339–342. doi: 10.1038/274339a0. [DOI] [PubMed] [Google Scholar]
  16. Hansch C., Dunn W. J., 3rd Linear relationships between lipophilic character and biological activity of drugs. J Pharm Sci. 1972 Jan;61(1):1–19. doi: 10.1002/jps.2600610102. [DOI] [PubMed] [Google Scholar]
  17. Israelachvili J. N., Marcelja S., Horn R. G. Physical principles of membrane organization. Q Rev Biophys. 1980 May;13(2):121–200. doi: 10.1017/s0033583500001645. [DOI] [PubMed] [Google Scholar]
  18. Jain M. K., Wray L. V., Jr Partition coefficients of alkanols in lipid bilayer/water. Biochem Pharmacol. 1978;27(8):1294–1295. doi: 10.1016/0006-2952(78)90469-0. [DOI] [PubMed] [Google Scholar]
  19. Janoff A. S., Pringle M. J., Miller K. W. Correlation of general anesthetic potency with solubility in membranes. Biochim Biophys Acta. 1981 Nov 20;649(1):125–128. doi: 10.1016/0005-2736(81)90017-1. [DOI] [PubMed] [Google Scholar]
  20. Koblin D. D., Chortkoff B. S., Laster M. J., Eger E. I., 2nd, Halsey M. J., Ionescu P. Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis. Anesth Analg. 1994 Dec;79(6):1043–1048. doi: 10.1213/00000539-199412000-00004. [DOI] [PubMed] [Google Scholar]
  21. Krasowski M. D., Harrison N. L. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278–1303. doi: 10.1007/s000180050371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu J., Laster M. J., Koblin D. D., Eger E. I., 2nd, Halsey M. J., Taheri S., Chortkoff B. A cutoff in potency exists in the perfluoroalkanes. Anesth Analg. 1994 Aug;79(2):238–244. doi: 10.1213/00000539-199408000-00006. [DOI] [PubMed] [Google Scholar]
  23. Liu J., Laster M. J., Taheri S., Eger E. I., 2nd, Chortkoff B., Halsey M. J. Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis. Anesth Analg. 1994 Dec;79(6):1049–1055. doi: 10.1213/00000539-199412000-00005. [DOI] [PubMed] [Google Scholar]
  24. Liu J., Laster M. J., Taheri S., Eger E. I., 2nd, Koblin D. D., Halsey M. J. Is there a cutoff in anesthetic potency for the normal alkanes? Anesth Analg. 1993 Jul;77(1):12–18. doi: 10.1213/00000539-199307000-00004. [DOI] [PubMed] [Google Scholar]
  25. Lundbaek J. A., Andersen O. S. Spring constants for channel-induced lipid bilayer deformations. Estimates using gramicidin channels. Biophys J. 1999 Feb;76(2):889–895. doi: 10.1016/S0006-3495(99)77252-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mascia M. P., Trudell J. R., Harris R. A. Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9305–9310. doi: 10.1073/pnas.160128797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miller K. W., Paton W. D., Smith E. B., Smith R. A. Physicochemical approaches to the mode of action of general anesthetics. Anesthesiology. 1972 Apr;36(4):339–351. doi: 10.1097/00000542-197204000-00008. [DOI] [PubMed] [Google Scholar]
  28. Miller K. W. The nature of the site of general anesthesia. Int Rev Neurobiol. 1985;27:1–61. doi: 10.1016/s0074-7742(08)60555-3. [DOI] [PubMed] [Google Scholar]
  29. Morein S., Andersson A., Rilfors L., Lindblom G. Wild-type Escherichia coli cells regulate the membrane lipid composition in a "window" between gel and non-lamellar structures. J Biol Chem. 1996 Mar 22;271(12):6801–6809. doi: 10.1074/jbc.271.12.6801. [DOI] [PubMed] [Google Scholar]
  30. Moss G. W., Curry S., Franks N. P., Lieb W. R. Mapping the polarity profiles of general anesthetic target sites using n-alkane-(alpha, omega)-diols. Biochemistry. 1991 Oct 29;30(43):10551–10557. doi: 10.1021/bi00107a026. [DOI] [PubMed] [Google Scholar]
  31. Mouritsen O. G., Bloom M. Models of lipid-protein interactions in membranes. Annu Rev Biophys Biomol Struct. 1993;22:145–171. doi: 10.1146/annurev.bb.22.060193.001045. [DOI] [PubMed] [Google Scholar]
  32. Mouritsen O. G., Jørgensen K. Small-scale lipid-membrane structure: simulation versus experiment. Curr Opin Struct Biol. 1997 Aug;7(4):518–527. doi: 10.1016/s0959-440x(97)80116-9. [DOI] [PubMed] [Google Scholar]
  33. Nielsen C., Goulian M., Andersen O. S. Energetics of inclusion-induced bilayer deformations. Biophys J. 1998 Apr;74(4):1966–1983. doi: 10.1016/S0006-3495(98)77904-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. North C., Cafiso D. S. Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency. Biophys J. 1997 Apr;72(4):1754–1761. doi: 10.1016/S0006-3495(97)78821-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Popot J. L., Engelman D. M. Helical membrane protein folding, stability, and evolution. Annu Rev Biochem. 2000;69:881–922. doi: 10.1146/annurev.biochem.69.1.881. [DOI] [PubMed] [Google Scholar]
  36. Pratt M. B., Husain S. S., Miller K. W., Cohen J. B. Identification of sites of incorporation in the nicotinic acetylcholine receptor of a photoactivatible general anesthetic. J Biol Chem. 2000 Sep 22;275(38):29441–29451. doi: 10.1074/jbc.M004710200. [DOI] [PubMed] [Google Scholar]
  37. Pringle M. J., Brown K. B., Miller K. W. Can the lipid theories of anesthesia account for the cutoff in anesthetic potency in homologous series of alcohols? Mol Pharmacol. 1981 Jan;19(1):49–55. [PubMed] [Google Scholar]
  38. Qin Z., Szabo G., Cafiso D. S. Anesthetics reduce the magnitude of the membrane dipole potential. Measurements in lipid vesicles using voltage-sensitive spin probes. Biochemistry. 1995 Apr 25;34(16):5536–5543. doi: 10.1021/bi00016a027. [DOI] [PubMed] [Google Scholar]
  39. Seddon J. M. Structure of the inverted hexagonal (HII) phase, and non-lamellar phase transitions of lipids. Biochim Biophys Acta. 1990 Feb 28;1031(1):1–69. doi: 10.1016/0304-4157(90)90002-t. [DOI] [PubMed] [Google Scholar]
  40. Stigter D., Mingins J., Dill K. A. Phospholipid interactions in model membrane systems. II. Theory. Biophys J. 1992 Jun;61(6):1616–1629. doi: 10.1016/S0006-3495(92)81965-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Taheri S., Halsey M. J., Liu J., Eger E. I., 2nd, Koblin D. D., Laster M. J. What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs? Anesth Analg. 1991 May;72(5):627–634. doi: 10.1213/00000539-199105000-00010. [DOI] [PubMed] [Google Scholar]
  42. Tang P., Yan B., Xu Y. Different distribution of fluorinated anesthetics and nonanesthetics in model membrane: a 19F NMR study. Biophys J. 1997 Apr;72(4):1676–1682. doi: 10.1016/S0006-3495(97)78813-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tieleman D. P., Marrink S. J., Berendsen H. J. A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biochim Biophys Acta. 1997 Nov 21;1331(3):235–270. doi: 10.1016/s0304-4157(97)00008-7. [DOI] [PubMed] [Google Scholar]
  44. Ueno S., Trudell J. R., Eger E. I., 2nd, Harris R. A. Actions of fluorinated alkanols on GABA(A) receptors: relevance to theories of narcosis. Anesth Analg. 1999 Apr;88(4):877–883. doi: 10.1097/00000539-199904000-00036. [DOI] [PubMed] [Google Scholar]
  45. Unwin N. Acetylcholine receptor channel imaged in the open state. Nature. 1995 Jan 5;373(6509):37–43. doi: 10.1038/373037a0. [DOI] [PubMed] [Google Scholar]
  46. Unwin N. Nicotinic acetylcholine receptor at 9 A resolution. J Mol Biol. 1993 Feb 20;229(4):1101–1124. doi: 10.1006/jmbi.1993.1107. [DOI] [PubMed] [Google Scholar]
  47. Vaes W. H., Ramos E. U., Hamwijk C., van Holsteijn I., Blaauboer B. J., Seinen W., Verhaar H. J., Hermens J. L. Solid phase microextraction as a tool to determine membrane/water partition coefficients and bioavailable concentrations in in vitro systems. Chem Res Toxicol. 1997 Oct;10(10):1067–1072. doi: 10.1021/tx970109t. [DOI] [PubMed] [Google Scholar]
  48. Xiang T. X., Anderson B. D. Molecular distributions in interphases: statistical mechanical theory combined with molecular dynamics simulation of a model lipid bilayer. Biophys J. 1994 Mar;66(3 Pt 1):561–572. doi: 10.1016/s0006-3495(94)80833-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. de Kruijff B. Lipid polymorphism and biomembrane function. Curr Opin Chem Biol. 1997 Dec;1(4):564–569. doi: 10.1016/s1367-5931(97)80053-1. [DOI] [PubMed] [Google Scholar]

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