PMID- 21965364 OWN - NLM STAT- MEDLINE DCOM- 20121009 LR - 20211020 IS - 1526-7598 (Electronic) IS - 0003-2999 (Print) IS - 0003-2999 (Linking) VI - 115 IP - 2 DP - 2012 Aug TI - In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate. PG - 297-304 LID - 10.1213/ANE.0b013e3182320559 [doi] AB - 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 11beta-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 gamma-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 muM and its EC(50) for LORR in rats was 13 +/- 5 mg/kg. At 13 muM, 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. FAU - Pejo, Ervin AU - Pejo E AD - Massachusetts General Hospital, Boston, MA, USA. FAU - Cotten, Joseph F AU - Cotten JF FAU - Kelly, Elizabeth W AU - Kelly EW FAU - Le Ge, Ri AU - Le Ge R FAU - Cuny, Gregory D AU - Cuny GD FAU - Laha, Joydev K AU - Laha JK FAU - Liu, Jifeng AU - Liu J FAU - Lin, Xiang Jie AU - Lin XJ FAU - Raines, Douglas E AU - Raines DE LA - eng GR - K08 GM083216/GM/NIGMS NIH HHS/United States GR - R21 DA029253-01/DA/NIDA NIH HHS/United States GR - R01 GM087316-02/GM/NIGMS NIH HHS/United States GR - R01 GM087316-01A1/GM/NIGMS NIH HHS/United States GR - R21 DA029253-02/DA/NIDA NIH HHS/United States GR - R01 GM087316/GM/NIGMS NIH HHS/United States GR - R21 DA029253/DA/NIDA NIH HHS/United States GR - R01 GM087316-03/GM/NIGMS NIH HHS/United States PT - Comparative Study PT - Journal Article DEP - 20110929 PL - United States TA - Anesth Analg JT - Anesthesia and analgesia JID - 1310650 RN - 0 (GABA-A Receptor Agonists) RN - 0 (Hypnotics and Sedatives) RN - 0 (Octanols) RN - 0 (Pyrroles) RN - 0 (Receptors, GABA-A) RN - 0 (carboetomidate) RN - 0 (methoxycarbonylethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate) RN - 059QF0KO0R (Water) RN - Z22628B598 (Etomidate) SB - IM MH - Adrenal Cortex/*drug effects/metabolism MH - Animals MH - Blood Pressure/*drug effects MH - Chromatography, High Pressure Liquid MH - Dose-Response Relationship, Drug MH - Drug Stability MH - Etomidate/analogs & derivatives/blood/chemical synthesis/*pharmacology MH - GABA-A Receptor Agonists/blood/chemical synthesis/*pharmacology MH - Hypnotics and Sedatives/blood/chemical synthesis/*pharmacology MH - Larva MH - Male MH - Membrane Potentials MH - Molecular Structure MH - Octanols/chemistry MH - Patch-Clamp Techniques MH - Pyrroles/blood/chemical synthesis/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, GABA-A/*drug effects/metabolism MH - Reflex/*drug effects MH - Structure-Activity Relationship MH - Time Factors MH - Water/chemistry MH - Xenopus laevis/embryology PMC - PMC3252484 MID - NIHMS324029 COIS- DISCLOSURES Name: Ervin Pejo, B.S. Contribution: EP led in conduct of study and manuscript preparation. He attests to the integrity of the data and analysis. Conflicts: EP has no conflicts of interest to declare. Name: Joseph F. Cotten M.D., Ph.D. Contribution: JFC assisted in study design, data interpretation, and manuscript preparation. Conflicts: JFC is a co-inventor on a patent application submitted by the Massachusetts General Hospital. He, his department, his laboratory, and his institution could receive royalties relating to the development of methoxycarbonyl-carboetomidate or related analogs. Name: Elizabeth W. Kelly Contribution: EWK performed the electrophysiology experiments Conflicts: EWK has no conflicts of interest to declare. Name: Ri Le Ge, M.D., Ph.D. Contribution: RLG assisted in study conduct. Conflicts: RLG has no conflicts of interest to declare. Name: Gregory D. Cuny, Ph.D. Contribution: GDC designed the synthetic pathways for the syntheses of methoxycarbonyl-carboetomidate and carboetomidate. Conflicts: GDC is a co-inventor on a patent application submitted by the Massachusetts General Hospital. He, his department, his laboratory, and his institution could receive royalties relating to the development of methoxycarbonyl-carboetomidate or related analogs. Name: Joydev K. Laha Ph.D. Contribution: JKL help to design the synthetic pathways for the syntheses of methoxycarbonyl-carboetomidate and carboetomidate. Conflicts: JKL has no conflicts of interest to declare. Name: Jifeng Liu, Ph.D. Contribution: JL oversaw the synthesis and purification of methoxycarbonyl-carboetomidate and carboetomidate. Conflicts: JL has no conflicts of interest to declare. Name: Xiang Jie Lin, MSc Contribution: XJL performed the synthesis and purification of methoxycarbonyl-carboetomidate and carboetomidate. Conflicts: XJL has no conflicts of interest to declare. Name: Douglas E. Raines, M.D. Contribution: DER conceived of methoxycarbonyl-carboetomidate, assisted in study design, data interpretation, and manuscript preparation. Attestation: Dr. Raines attests to the integrity of the data and analysis. Conflicts: DER is a co-inventor on a patent application submitted by the Massachusetts General Hospital. He, his department, his laboratory, and his institution could receive royalties relating to the development of methoxycarbonyl-carboetomidate or related analogs. DER holds an equity position in Annovation BioPharma, a pharmaceutical company that seeks to develop technologies covered by that patent. This manuscript was handled by: Marcel E. Durieux, MD, PhD EDAT- 2011/10/04 06:00 MHDA- 2012/10/10 06:00 PMCR- 2013/08/01 CRDT- 2011/10/04 06:00 PHST- 2011/10/04 06:00 [entrez] PHST- 2011/10/04 06:00 [pubmed] PHST- 2012/10/10 06:00 [medline] PHST- 2013/08/01 00:00 [pmc-release] AID - ANE.0b013e3182320559 [pii] AID - 10.1213/ANE.0b013e3182320559 [doi] PST - ppublish SO - Anesth Analg. 2012 Aug;115(2):297-304. doi: 10.1213/ANE.0b013e3182320559. Epub 2011 Sep 29.