title: γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs.
abstract: BACKGROUND
  Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. The authors characterized the GABAA receptor and hypnotic potencies of etomidate analogs. The authors then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogs to their structures to identify the specific molecular determinants of potency.
  
  
  METHODS
  GABAA receptor potencies were defined with voltage clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1[L264T]) that enhances anesthetic sensitivity (n = 36 to 60 measurements per concentration-response curve). The hypnotic potencies of etomidate analogs were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 to 21 measurements per dose-response curve). Three-dimensional quantitative structure-activity relationships were determined in silico using comparative molecular field analysis.
  
  
  RESULTS
  The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogs ranged by 91- and 53-fold, respectively. These potency measurements were significantly correlated (r = 0.72), but neither measurement correlated with drug hydrophobicity (r = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated, and a pharmacophore model was built that revealed both the structural elements in etomidate analogs associated with high potency and the interactions that these elements make with the etomidate-binding site.
  
  
  CONCLUSIONS
  There are multiple specific structural elements in etomidate and etomidate analogs that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more.
authors.affiliation: From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (E.P., P.S., P.D., S.S.H., D.E.R.); and Certara L.P., St. Louis, Missouri (L.W.).
authors.forename: Ervin
authors.initials: E
authors.lastname: Pejo
authors.forename: Peter
authors.initials: P
authors.lastname: Santer
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Dershwitz
authors.forename: S Shaukat
authors.initials: SS
authors.lastname: Husain
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005045:Etomidate