Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology
Language: 
English
Short Title: 
Analogues of etomidate
Abstract: 

BACKGROUND: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure-activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate's chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). METHODS: The ?-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed ?1(L264T)?3?2L and ?1(L264T)?1?2L ?-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). RESULTS: All four drugs activated both ?-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest ?-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing ?3 subunits than ?1 subunits; however, dihydrogen etomidate's subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. CONCLUSION: The linkage between the structure of etomidate's chiral center and its pharmacology suggests that altering etomidate's chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.

Author(s): 
Pejo, Ervin
Santer, Peter
Jeffrey, Spencer
Gallin, Hilary
Husain, S. Shaukat
Raines, Douglas E.
Item Type: 
Journal Article
Publication Title: 
Anesthesiology
Journal Abbreviation: 
Anesthesiology
Publication Date: 
8/14/2015
Publication Year: 
2014
Pages: 
290-301
Volume: 
121
Issue: 
2
ISSN: 
1528-1175
DOI: 
10.1097/ALN.0000000000000268
Library Catalog: 
PubMed
Extra: 
PMID: 24777068 PMCID: PMC4121658

Turabian/Chicago Citation

Ervin Pejo, Peter Santer, Spencer Jeffrey, Hilary Gallin, S. Shaukat Husain and Douglas E. Raines. 8/14/2015. "Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology." Anesthesiology 121: 2: 290-301. 10.1097/ALN.0000000000000268.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1097/ALN.0000000000000268 | issn = 1528-1175 | volume = 121 | pages = 290-301 | last = Pejo | first = Ervin | coauthors = Santer, Peter, Jeffrey, Spencer, Gallin, Hilary, Husain, S. Shaukat, Raines, Douglas E. | title = Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology | journal = Anesthesiology | date = 8/14/2015 | pmid = | pmc = }} </ref>