title: Inhibition of human alpha4beta2 neuronal nicotinic acetylcholine receptors by volatile aromatic anesthetics depends on drug hydrophobicity.
abstract: BACKGROUND
  Volatile aromatic compounds such as benzene are general anesthetics that cause amnesia, hypnosis, and immobility in response to noxious stimuli when inhaled. Although these compounds are not used clinically, they are frequently found in commercial items such as solvents and household cleaning products and are abused as inhalant drugs. Volatile aromatic anesthetics are useful pharmacological tools for probing the relationship between chemical structure and drug activity at putative general anesthetic targets. Neuronal nicotinic acetylcholine (nACh) receptors are ligand-gated ion channels widely expressed in the brain, which are thought to play important roles in learning and memory. In this study, we tested the hypothesis that aromatic anesthetics reversibly inhibit alpha(4)beta(2) neuronal nACh receptor function and sought to determine the structural correlates of receptor inhibition.
  
  
  METHODS
  Electrophysiological techniques were used to quantify the effects of 8 volatile aromatic anesthetics on currents elicited by 1 mM ACh and mediated by human alpha(4)beta(2) nACh receptors expressed in Xenopus oocytes.
  
  
  RESULTS
  All of the volatile aromatic anesthetics used in this study reversibly inhibited alpha(4)beta(2) nACh receptors with IC(50) values ranging from 0.00091 atm for 1,2-difluorobenzene to 0.045 atm for hexafluorobenzene. With the exception of hexafluorobenzene, all of the compounds had IC(50) values less than minimum alveolar concentration. Inhibitory potency correlated poorly with the cation-pi binding energies of the compounds (r(2) = 0.48, P = 0.059). However, there was a good correlation between inhibitory potency and the octanol/gas partition coefficient (r(2) = 0.87, P = 0.0008).
  
  
  CONCLUSIONS
  Volatile aromatic anesthetics potently and reversibly inhibit human alpha(4)beta(2) neuronal nACh receptors. This inhibition may play a role in producing amnesia. In contrast to N-methyl-d-aspartate receptors, the inhibitory potencies of aromatic anesthetics for alpha(4)beta(2) neuronal nACh receptors seem to be dependent on drug hydrophobicity rather than electrostatic properties. This implies that the volatile aromatic anesthetic binding site in the alpha(4)beta(2) neuronal nACh receptor is hydrophobic in character and differs from the nature of the binding site in N-methyl-D-aspartate receptors.
authors.affiliation: Department of Anaesthesia, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ksolt@partners.or
authors.forename: Ken
authors.initials: K
authors.lastname: Solt
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Kelly
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cotten
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D018685:Anesthetics, Inhalation; D001555:Benzene Derivatives; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2