Discovery of thioetomidate derivatives as rapid recovery hypnotics without adrenocortical suppression

Intravenous anesthetics play a crucial role during surgery. Etomidate, a commonly used intravenous anesthetic agent, is prized for its rapid onset and smooth induction of anesthesia. However, it has a pronounced adverse effect on adrenal function suppression. To obtain new rapid recovery hypnotic agents without adrenocortical suppression, a series of thioetomidate derivatives (TET-1-TET-14) were designed and synthesized. Among them, TET-13 (half-live T_1/2 = 0.48 min) was metabolized much faster than that of etomidate (T_1/2 = 26 min) in rat plasma. In rodents, TET-13 exhibited potent anesthetic effects in both mice (ED₅₀ = 0.48 mg/kg) and rats (ED₅₀ = 0.69 mg/kg) and demonstrated a markedly shorter recovery time compared to etomidate. In the GABA_AR binding assay, TET-13 acted as a positive allosteric modulator on the GABA_A receptor and showed an EC₅₀ of 5.65 μM which was lower than etomidate (EC₅₀ = 9.29 μM). At equivalent doses, TET-13 group showed significantly less adrenocortical suppression than etomidate. Moreover, in the continuous infusion test, the time to behavioral recovery and time to walk after infusion with TET-13 were all shorter than etomidate. Thioetomidate derivatives represent a promising strategy to develop new rapid recovery hypnotic agents without adrenocortical suppression.