Abstract
General anesthetics apparently act through weak, noncovalent and reversible interactions with certain sites in appropriate brain proteins. As a means of gaining insight into the factors underlying anesthetic potency, we have analyzed the computed electrostatic potentials V S(r) on the surfaces of 20 molecules with activities that vary between zero and high. Our results are fully consistent with, and help to interpret, what has been observed experimentally. We find that an intermediate level of internal charge separation is required; this is measured by Π, the average absolute deviation of V S(r), and the approximate window is 7 < Π < 13 kcal mol−1. This fits in well with the fact that anesthetics need to be lipid soluble, but also to have some degree of hydrophilicity. We further show that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, V S,max, associated with their hydrogens, chlorines and bromines (but not fluorines). These positive sites may impede the functioning of key brain proteins, for example by disrupting their normal hydrogen-bond patterns. It has indeed been recognized for some time that the most active polyhalogenated alkanes and ethers contain hydrogens usually in combination with chlorines and/or bromines.
Similar content being viewed by others
References
Sandorfy C (2005) Collect Czechoslov Chem Commun 70:539–549
Meyer HH (1899) Arch Exp Pathol Pharmakol 42:109–115
Overton EL (1901) Studien über die Narkose zugleich ein Beitrag zur allemeinen Pharmacologie. Fischer G, Jena
Carpenter FG (1954) Am J Physiol 178:505–509
Adriani J (1962) Chemistry and Physics of Anesthesia. Thomas CC, Springfield, IL (ch 27)
Miller KW, Paton WDM, Smith EB (1965) Nature 206:574–577
Eger EI II, Brandstater B, Saidman LJ, Regan MJ, Severinghaus JW, Munson ES (1965) Anesthesiology 26:771–777
Halsey MJ, Kent DW (1972) Anesthesiology 36:313–315
Miller KW, Paton WDM, Smith EB, Smith RA (1972) Anesthesiology 36:339–351
Miller KW (1985) Int Rev Neurobiol 27:1–61
Koblin DD, Chortkoff BS, Laster MJ, Eger EI II, Halsey MJ, Ionescu P (1994) Anaesth Analg 79:1043–1048
Koblin DD, Laster MJ, Ionescu P, Gong D, Eger EI II, Halsey MJ, Hudlicky T (1999) Anaesth Analg 88:1161–1167
Ueda I, Matsuki H, Kaminoh Y, Kaneshina S, Kamaya H (2000) Prog Anesth Mech Jpn 6:207–212
Urban BW, Bleckwenn M (2002) Br J Anaesth 89:3–16
Buchet R, Sandorfy C (1985) Biophys Chemist 22:249–254
Pohorille A, Cieplak P, Wilson MA (1996) Chem Phys 204:337–345
Eger EI, Koblin DD, Harris RA, Kendig JJ, Pohorille A, Halsey MJ, Trudell JR (1997) Anaesth Analg 84:915–918
Pohorille A, Wilson MA (1996) J Chem Phys 104:3760–3773
Sandorfy C (2000) Prog Anesth Mech Jpn 6:34–39 (Special Issue)
Eger EI (2004) Am J Health Syst Pharm 61(Suppl 4):S3–S10
Trudell JR, Bertaccini E (2002) Br J Anaesth 89:32–40
Stewart RF (1972) J Chem Phys 57:1664–1668
Politzer P, Truhlar DG (eds) (1981) Chemical applications of atomic and molecular electrostatic potentials. Plenum Press, New York
Naray-Szabo G, Ferenczy GG (1995) Chem Rev 95:829–847
Politzer P, Murray JS (1991) In: Lipkowitz KB, Boyd DB (eds) Reviews in Computational Chemistry, vol 2. VCH Publishers, New York, (ch 7)
Murray JS, Politzer P (1998) J Mol Struct Theochem 425:107–114
Politzer P, Murray JS (1999) Trends Chem Phys 7:157–165
Politzer P, Murray JS, Peralta-Inga Z (2001) Int J Quantum Chem 85:676–684
Bader RFW, Carroll MT, Cheeseman JR, Chang C (1987) J Am Chem Soc 109:7968–7979
Brinck T, Murray JS, Politzer P (1992) Mol Phys 76:609–617
Hagelin H, Brinck T, Berthelot M, Murray JS, Politzer P (1995) Can J Chem 73:483–488
Park JD, Stricklin B, Lacher JR (1954) J Am Chem Soc 76:1387–1388
Larsen ER (1969) Fluorine Chem Rev 3:1–44
Terrell RC, Speers L, Szur AJ, Treadwell J, Ucciardi TR (1971) J Med Chem 14:517–519
Terrell RC, Speers L, Szur AJ, Ucciardi T, Vitcha JF (1972) J Med Chem 15:606–608
Brinck T, Murray JS, Politzer P (1992) Int J Quantum Chem Quantum Biol Symp 19:57–64
Murray JS, Paulsen K, Politzer P (1994) Proc Indian Acad Sci (Chem Sci) 106:267–275
Auffinger P, Hays FA, Westhof E, Shing Ho P (2004) Proc Natl Acad Sci 101:16789–16794
Politzer P, Lane P, Concha MC, Ma Y, Murray JS (2006) J Mol Mod DOI 10.1007/s00894-006-0154-7
Clark T, Hennemann M, Murray JS, Politzer P (2006) J Mol Mod DOI 10.1007/s00894-006-0130-2
Bent HA (1968) Chem Rev 68:587–648
Dumas J-M, Peurichard H, Gomel M (1978) J Chem Res (S)54–55
Ramasubbu N, Parthasarathy R, Murray-Rust P (1986) J Am Chem Soc 108:4308–4314
Metrangolo P, Neukirch H, Pilati T, Resnati G (2005) Acc Chem Res 38:386–395
Bacher A, Burton AW, Uchida T, Zornow MH (1997) Anaesth Analg 85:1203–1206
Targ AG, Yasuda N, Eger EI II, Huang G, Vernice GG, Terrel RC, Koblin DD (1989) Anaesth Analg 68:599–602
Di Paolo T, Sandorfy C (1974) Nature 252:471–472
Bernard-Houplain M-C, Sandorfy C (1973) Can J Chem 51:1075–1082
Bernard-Houplain M-C, Sandorfy C (1973) Can J Chem 3640–3646
Di Paolo T, Sandorfy C (1974) Chem Phys Lett 26:466–469
Di Paolo T, Sandorfy C (1974) Can J Chem 52:3612–3622
Wulf RJ, Featherstone RM (1957) Anesthiology 18:97–105
Koski WS, Kaufman JJ, Wilson KM (1973) Nature 242:65–66
Stewart JJP (1990) J Comput-Aided Mol Des 4:1–8
Tang P, Zubryzcki I, Xu Y (2001) J Comput Chem 22:436–444
Acknowledgement
We would like to thank Mr. Alfred Politzer for his assistance with this work.
Author information
Authors and Affiliations
Corresponding author
Additional information
Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005.
Rights and permissions
About this article
Cite this article
Trogdon, G., Murray, J.S., Concha, M.C. et al. Molecular surface electrostatic potentials and anesthetic activity. J Mol Model 13, 313–318 (2007). https://doi.org/10.1007/s00894-006-0145-8
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-006-0145-8