The pyrrole etomidate analog carboetomidate potently inhibits human 5-HT3A receptor function: comparisons with...

5-Hydroxytryptamine type 3 (5-HT(3)) receptors are excitatory ion channels belonging to the cys-loop family of ligand-gated ion channels. They are involved in nausea and vomiting and their antagonists are used clinically as antiemetic drugs. We previously reported the development of a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties, but lacks its potent inhibitory effect on adrenocorticotropic hormone-stimulated steroid synthesis. Also in contrast to etomidate, carboetomidate potently inhibits nicotinic acetylcholine receptors. Because nicotinic acetylcholine and 5-HT(3) receptors are highly homologous, we hypothesized that carboetomidate might also potently inhibit 5-HT(3) receptors with potentially important implications for the drug's emetogenic activity. In the current studies, we investigated and compared modulation of 5-HT(3A) receptors by carboetomidate and etomidate.

5-HT(3) receptors were heterologously expressed in human embryonic kidney cells. Drugs were applied with a multichannel superfusion pipette coupled to piezoelectric elements, and currents were recorded from cells in either the whole-cell or excised outside-out patch configuration of patch-clamp recordings.

Carboetomidate and etomidate inhibited integrated 5-HT(3A) receptor-mediated currents with respective half-inhibitory concentrations of 1.9 μM (95% confidence interval [CI] = 1.4-2.7 μM) and 25 μM (95% CI = 17-37 μM). These values may be compared with respective hypnotic concentrations of 5.4 and 2.3 µM. This inhibition reflected hypnotic effects on peak current amplitudes and desensitization rates. Half-inhibitory concentrations for reducing peak current amplitudes were 34 μM (95% CI = 24-48 µM) for carboetomidate and 171 μM (95% CI = 128-228 µM) for etomidate. Half-inhibitory concentrations for reducing the desensitization time constant were 3.5 μM (95% CI = 2.4-5.1 µM) for carboetomidate and 36 μM (95% CI = 21-59 µM) for etomidate.

In contrast to etomidate, carboetomidate inhibits 5-HT(3A) receptor-mediated currents at hypnotic concentrations. This inhibition is primarily the result of enhancing the rate of desensitization. Because carboetomidate potently inhibits 5-HT(3A) receptors, it may be less emetogenic than etomidate.