Role of hydrogen bonding in general anesthesia

J Pharm Sci. 1991 Aug;80(8):719-24. doi: 10.1002/jps.2600800802.


The importance of hydrogen bonding in determining the potency of a general anesthetic is controversial. In order to investigate the role of hydrogen bonding further, we have used a multiple linear regression approach to quantify the relative importance of various physical properties of an anesthetic molecule (i.e., its ability to donate or accept a hydrogen bond, its dipolarity and polarizability, and its size) in determining its anesthetic potency. For comparison, we have applied the same approach to partitioning between water and three simple, but contrasting solvents (n-octanol, n-hexadecane, and N,N-dimethylacetamide) and to inhibition of an enzyme (firefly luciferase) which mimics many of the properties of general anesthetic target sites in animals. We present equations which accurately predict potencies (over many orders of magnitude) for producing general anesthesia and inhibiting the firefly luciferase enzyme. We find that the aqueous potency (defined as the reciprocal of the aqueous EC50 concentration) of a molecule as a general anesthetic or an inhibitor of luciferase is determined overwhelmingly by its size (which increases potency) and its ability to accept a hydrogen bond (which decreases potency), but only marginally by its ability to donate a hydrogen bond or by its dipolarity and polarizability. We conclude that general anesthetic target sites in animals must have, in addition to their overall hydrophobicity, a polar component which is a relatively poor hydrogen bond donor, but which can accept a hydrogen bond about as well as water.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Anesthesia, General*
  • Anesthetics / chemistry
  • Anesthetics / pharmacology*
  • Animals
  • Anura
  • Chemical Phenomena
  • Chemistry, Physical
  • Firefly Luciferin / chemistry
  • Hydrogen Bonding
  • Luciferases / antagonists & inhibitors
  • Magnesium Sulfate / chemistry
  • Mice
  • Solvents


  • Anesthetics
  • Solvents
  • Firefly Luciferin
  • Magnesium Sulfate
  • Adenosine Triphosphate
  • Luciferases