The Pyrrole Etomidate Analog Carboetomidate Potently Inhibits Human 5-HT3A Receptor Function: Comparisons with Etomidate and Potential Implications for Emetogenesis

BACKGROUND: 5-Hydroxytryptamine type 3 (5-HT3) 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-HT3 receptors are highly homologous, we hypothesized that carboetomidate might also potently inhibit 5-HT3 receptors with potentially important implications for the drug's emetogenic activity. In the current studies, we investigated and compared modulation of 5-HT3A receptors by carboetomidate and etomidate. METHODS: 5-HT3 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. RESULTS: Carboetomidate and etomidate inhibited integrated 5-HT3A receptor mediated currents with respective half-inhibitory concentrations of 1.9 mu M (95% confidence interval [CI] = 1.4-2.7 mu M) and 251 mu M (95% CI = 17-37 mu M). These values may be compared with respective hypnotic concentrations of 5.4 and 2.3 mu M. This inhibition reflected hypnotic effects on peak current amplitudes and desensitization rates. Half-inhibitory concentrations for reducing peak current amplitudes were 34 mu M (95% CI = 24-48 mu M) for carboetomidate and 171 mu M (95% CI = 128-228 mu M) for etomidate. Half-inhibitory concentrations for reducing the desensitization time constant were 3.5 mu M (95% CI = 2.4-5.1 mu M) for carboetomidate and 36 mu M (95% CI = 21-59 mu M) for etomidate. CONCLUSIONS: In contrast to etomidate, carboetomidate inhibits 5-HT3A receptor mediated currents at hypnotic concentrations. This inhibition is primarily the result of enhancing the rate of desensitization. Because carboetomidate potently inhibits 5-HT3A receptors, it may be less emetogenic than etomidate. (Anesth Analg 2013;116:573-9)