Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.

Abstract

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.

• Authors: Joseph F Cotten, Stuart A Forman, Joydev K Laha, Gregory D Cuny, S Shaukat Husain, Keith W Miller, Hieu H Nguyen, Elizabeth W Kelly, Deirdre Stewart, Aiping Liu, Douglas E Raines
• Journal: Anesthesiology (Anesthesiology) Vol. 112 Issue 3 Pg. 637-44 (Mar 2010) ISSN: 1528-1175 [Electronic] United States
• PMID: 20179500 (Publication Type: Journal Article)

Chemical References

• Hypnotics and Sedatives
• Pyrroles
• RNA, Messenger
• Receptors, GABA-A
• carboetomidate
• Hydrocortisone
• Etomidate

Topics

• Adrenal Cortex (drug effects)
• Adrenal Cortex Neoplasms (metabolism)
• Animals
• Drug Design
• Electrophysiology
• Etomidate (analogs & derivatives, pharmacology)
• Female
• Hemodynamics (drug effects)
• Hydrocortisone (biosynthesis)
• Hypnotics and Sedatives (pharmacology)
• Larva
• Male
• Postural Balance (drug effects)
• Pyrroles (chemical synthesis, pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (drug effects)
• Structure-Activity Relationship
• Xenopus laevis