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.

Figure 1

(A) Hypothesized attractive interaction between the basic nitrogen in etomidate’s imidazole ring and the heme iron at 11β-hydroxylase’s active site. (B) Structure of carboetomidate.

Figure 2

(A) Carboetomidate concentration-response curve for loss of righting reflex (LORR) in tadpoles. Each data point represents the result from a single tadpole. The curve is a fit of the data set using the method of Waud yielding an EC₅₀ of 5.4 ± 0.5 μM. (B) Carboetomidate dose-response curve for LORR in rats. Each data point represents the results from a single rat. The curve is a fit of the data set using the method of Waud yielding an ED₅₀ of 7 ± 2 mg/kg.

Figure 3

The duration loss of righting reflex (LORR) in rats increased with the logarithm of the carboetomidate dose. The slope of this relationship was 16 ± 4 min/(log mg/kg) (r² = 0.64).

Figure 4

Carboetomidate modulation of human γ-aminobutyric acid type A receptor function. (A) Representative traces showing reversible enhancement by 10 μM carboetomidate of currents mediated by wild-type receptors when evoked by EC_5-10 γ-aminobutyric acid. (B) Representative traces showing minimal of enhancement by 10 μM carboetomidate of currents mediated by etomidate-insensitive mutant receptors when evoked by EC_5-10 γ-aminobutyric acid.

Figure 5

The effects of 14 mg/kg carboetomidate (n=7), 2 mg/kg etomidate (n=6), and dimethyl sulfoxide (DMSO) vehicle alone (n=4) on mean blood pressure in rats. Hypnotics were given at doses equal to twice their respective ED₅₀s for loss of righting reflex in DMSO vehicle. All rats received the same quantity of DMSO vehicle (350 μl/kg). Hypnotic in DMSO vehicle or DMSO vehicle alone was injected at time 0. Each data point represents the average (± SD) change in mean blood pressure during each 30 s epoch. *, P < 0.05 versus DMSO vehicle alone.

Figure 6

The effects of carboetomidate and etomidate on cortisol synthesis by human adrenocortical carcinoma cells. The curves are fits of each data set to a Hill equation yielding half maximal inhibitory concentrations of 2.6 ± 1.5 μM and1.3 ± 0.2 nM for carboetomidate and etomidate, respectively. Each data point is the average (± SD) of three measurements. The control cortisol concentration was 0.86 ± 020 ng/ml.

Figure 7

Adrenocorticotropic hormone_1-24-stimulated serum corticosterone concentrations in rats 15 min after administration of vehicle, 2 mg/kg etomidate, or 14 mg/kg carboetomidate. Hypnotics were given at doses equal to twice their respective ED50s for loss of righting reflex. Four rats were studied in each group. Average serum corticosterone concentrations (± SD) were 390 ± 50 ng/ml, 120 ± 80 ng/ml, and 330 ± 70 ng/ml following administration of dimethyl sulfoxide vehicle (control), etomidate, and carboetomidate, respectively. *, P < 0.05, N.S., no significant difference.

Figure 8

Synthesis of carboetomidate