title: In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.
abstract: BACKGROUND
  We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11β-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate.
  
  
  METHODS
  MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC(50)) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on γ-aminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats.
  
  
  RESULTS
  MOC-carboetomidate's octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15,000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate's EC(50) for LORR in tadpoles was 9 ± 1 μM and its EC(50) for LORR in rats was 13 ± 5 mg/kg. At 13 μM, MOC-carboetomidate enhanced GABA(A) receptor currents by 400% ± 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs 15 ± 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone.
  
  
  CONCLUSIONS
  MOC-carboetomidate is a GABA(A) receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ervin
authors.initials: E
authors.lastname: Pejo
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cotten
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Kelly
authors.forename: Ri
authors.initials: R
authors.lastname: Le Ge
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Joydev K
authors.initials: JK
authors.lastname: Laha
authors.forename: Jifeng
authors.initials: J
authors.lastname: Liu
authors.forename: Xiang Jie
authors.initials: XJ
authors.lastname: Lin
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005045:Etomidate / Q000031:analogs & derivatives / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D007814:Larva; D008297:Male; D008564:Membrane Potentials; D015394:Molecular Structure; D000442:Octanols / Q000737:chemistry; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014867:Water / Q000737:chemistry; D014982:Xenopus laevis / Q000196:embryology
chemical_list: D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D000442:Octanols; D011758:Pyrroles; D011963:Receptors, GABA-A; C548177:carboetomidate; C575452:methoxycarbonylethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate; D014867:Water; D005045:Etomidate