Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology.
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 γ-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)β3γ2L and α1(L264T)β1γ2L γ-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 γ-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 γ-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 β3 subunits than β1 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.


CONCLUSIONS
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.
From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Ervin
E
Pejo
Peter
P
Santer
Spencer
S
Jeffrey
Hilary
H
Gallin
S Shaukat
SS
Husain
Douglas E
DE
Raines
D000302:Adrenal Cortex / Q000187:drug effects; D000303:Adrenal Cortex Diseases / Q000139:chemically induced / Q000473:pathology; D018686:Anesthetics, Intravenous / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002244:Carbon / Q000737:chemistry*; D005045:Etomidate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007928:Lethal Dose 50; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018686:Anesthetics, Intravenous; D018755:GABA Agonists; D006993:Hypnotics and Sedatives; D007202:Indicators and Reagents; D011963:Receptors, GABA-A; D002244:Carbon; D005045:Etomidate