title: AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.
abstract: BACKGROUND
  Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile.
  
  
  METHODS
  The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043.
  
  
  RESULTS
  AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration.
  
  
  CONCLUSIONS
  AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.
authors.affiliation: Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. talmage.egan@hsc.utah.edu
authors.forename: Talmage D
authors.initials: TD
authors.lastname: Egan
authors.forename: Shinju
authors.initials: S
authors.lastname: Obara
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jenkins
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Jaw-Tsai
authors.forename: Shanti
authors.initials: S
authors.lastname: Amagasu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Cook
authors.forename: Scott C
authors.initials: SC
authors.lastname: Steffensen
authors.forename: David T
authors.initials: DT
authors.lastname: Beattie
mesh_terms: D000762:Anesthesia Recovery Period; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D016292:Procedural Sedation; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010648:Phenylacetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
chemical_list: C573579:AZD-3043; D006993:Hypnotics and Sedatives; D010648:Phenylacetates; D011963:Receptors, GABA-A