Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.
BACKGROUND
Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11beta-hydroxylase.


METHODS
The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha1beta2gamma2l and etomidate-insensitive mutant alpha1beta2M286Wgamma2l human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats.


RESULTS
Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses.


CONCLUSIONS
Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
Cotten
Joseph F
JF
Harvard Medical School, Boston, Massachusetts, USA.
Forman
Stuart A
SA
Laha
Joydev K
JK
Cuny
Gregory D
GD
Husain
S Shaukat
SS
Miller
Keith W
KW
Nguyen
Hieu H
HH
Kelly
Elizabeth W
EW
Stewart
Deirdre
D
Liu
Aiping
A
Raines
Douglas E
DE
D000302:Adrenal Cortex / Q000187:drug effects*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D004594:Electrophysiology; D005045:Etomidate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006854:Hydrocortisone / Q000096:biosynthesis; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007814:Larva; D008297:Male; D004856:Postural Balance / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D006993:Hypnotics and Sedatives; D011758:Pyrroles; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C548177:carboetomidate; D006854:Hydrocortisone; D005045:Etomidate