List of etomidate analogues

Etomidate chemical structure.

Etomidate analogues, are a group of imidazole (and pyrrole, etc) derivatives typified by the sedative and hypnotic drug etomidate (brand name Amidate). Etomidate is widely used as a short-acting intravenous anaesthetic agent both for induction of anaesthesia prior to surgery, and for procedural sedation for more minor medical procedures. It acts as a positive allosteric modulator of GABAA receptors, selective for subtypes containing β2 and β3 subunits. Etomidate also suppresses corticosteroid synthesis in the adrenal cortex by inhibiting the enzyme 11β-hydroxylase, which is generally regarded as an unwanted side effect in its primary application as a sedative-hypnotic drug, but can be useful in the treatment of certain medical conditions such as Cushing's syndrome. In recent years, etomidate and related compounds have also become subject to recreational abuse primarily by vaping, and sold under names such as space oil or kpods. Consequently, a wide variety of etomidate analogues are now known. This includes derivatives developed for medical use which either seek to eliminate the suppression of corticosteroid synthesis and act purely as sedative-hypnotics, or conversely to selectively inhibit corticosteroid synthesis but without producing sedative-hypnotic effects. A second group of derivatives have been sold as designer drugs, where the main motivation is to find compounds which retain the desired sedative-hypnotic effects but with a modified chemical structure so as to evade legal controls on etomidate and other known older derivatives, which in most cases appear to retain both the sedative-hypnotic effects and also the suppression of corticosteroid synthesis. While the stereochemistry of some designer analogues has not been determined, in all derivatives for which pharmacological data is available the activity resides exclusively in the isomer where the alpha-methyl benzyl group is the (R) enantiomer.

Table of etomidate analogues

See also

References

  1. ↑ Zolle IM, Berger ML, Hammerschmidt F, Hahner S, Schirbel A, Peric-Simov B. New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues. J Med Chem. 2008 Apr 10;51(7):2244-53. doi:10.1021/jm800012w PMID 18348518
  2. ↑ Atucha E, Hammerschmidt F, Zolle I, Sieghart W, Berger ML. Structure-activity relationship of etomidate derivatives at the GABA(A) receptor: Comparison with binding to 11beta-hydroxylase. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4284-7. doi:10.1016/j.bmcl.2009.05.065 PMID 19497738
  3. ↑ Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology. 2011 Mar;114(3):695-707. doi:10.1097/ALN.0b013e3181ff72b5 PMID 21263301
  4. ↑ Sneyd JR (2012). "Novel etomidate derivatives". Current Pharmaceutical Design. 18 (38): 6253–6256. doi:10.2174/138161212803832362. PMID 22762475.
  5. ↑ Husain SS, Pejo E, Ge R, Raines DE. Modifying methoxycarbonyl etomidate inter-ester spacer optimizes in vitro metabolic stability and in vivo hypnotic potency and duration of action. Anesthesiology. 2012 Nov;117(5):1027-36. doi:10.1097/ALN.0b013e31826d3bef PMID 22929736
  6. ↑ Ge R, Pejo E, Husain SS, Cotten JF, Raines DE (November 2012). "Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs". Anesthesiology. 117 (5): 1037–1043. doi:10.1097/ALN.0b013e31826d3de2. PMC 3509380. PMID 22929726.
  7. ↑ Malapero RJ, Zaccagnino MP, Brovman EY, Kaye AD, Urman RD (2017). "Etomidate derivatives: Novel pharmaceutical agents in anesthesia". Journal of Anaesthesiology, Clinical Pharmacology. 33 (4): 429–431. doi:10.4103/0970-9185.222521. PMC 5791251. PMID 29416230.
  8. ↑ McGrath M, Yu Z, Jayakar SS, Ma C, Tolia M, Zhou X, et al. (November 2018). "Etomidate and Etomidate Analog Binding and Positive Modulation of γ-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect". Anesthesiology. 129 (5): 959–969. doi:10.1097/ALN.0000000000002356. PMC 6278829. PMID 30052529.
  9. ↑ Valk BI, Struys MM (October 2021). "Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics". Clinical Pharmacokinetics. 60 (10): 1253–1269. doi:10.1007/s40262-021-01038-6. PMC 8505283. PMID 34060021.
  10. ↑ Philip AB, Brohan J, Goudra B (January 2025). "The Role of GABA Receptors in Anesthesia and Sedation: An Updated Review". CNS Drugs. 39 (1): 39–54. doi:10.1007/s40263-024-01128-6. PMC 11695389. PMID 39465449.
  11. ↑ Chen Y, Wu L, Lang B, Zhang W, Chen S (14 October 2025). "Recent progress in the development of etomidate analogues". Frontiers in Pharmacology. 16 1614865. doi:10.3389/fphar.2025.1614865. PMC 12558937. PMID 41164750.
  12. ↑ Fan Y, Chen X, Wu H, Ke X, Chen H, Xu Y, et al. (November 2025). "Leveraging mass spectrometry fragmentation patterns for accelerated screening and structural elucidation of new etomidate analogues in suspect samples". Journal of Pharmaceutical and Biomedical Analysis. 265 117023. doi:10.1016/j.jpba.2025.117023. PMID 40532400.
  13. ↑ Bai S, Qian Z, Chen Y, Liu S, Wang F, Liu F (September 2025). "Traceability of etomidate and its analogs in biological samples using "specific" metabolites". Analytical Methods. 17 (36): 7207–7216. doi:10.1039/D5AY00773A. PMID 40879556.
  14. ↑ Bai S, Li M, Tang S, Wan S, Wu R, Chen L, et al. (2025). "Drug substitutes - Insights on benefits, risks, detection methods, and management strategies: a systematic review". Frontiers in Psychiatry. 16 1600212. doi:10.3389/fpsyt.2025.1600212. PMC 12310920. PMID 40747264.
  15. ↑ Stojanovic M, Pejcic N, Jankovic R (August 2026). "What's new in intravenous anaesthesia?". Current Opinion in Anaesthesiology. 39 (4): 469–473. doi:10.1097/ACO.0000000000001622. PMID 41677226.
  16. ↑ Xin L, Deying G, Yi K, Qingrong Q, Jun Y. Synthesis, metabolism in vitro and pharmacodynamic evaluation of etomidate soft analog ET-25-2. West China J. Pharm. Sci 2023; 38(02): 133–137. doi:10.13375/j.cnki.wcjps.2023.02.003
  17. ↑ Zhu J, Jiang X, Li Z, Liu S, Han J, Li S, Liu Z, Zhuang T, Zhang G. Discovery of thioetomidate derivatives as rapid recovery hypnotics without adrenocortical suppression. Bioorganic chemistry. 2025; 154: 107997. doi:10.1016/j.bioorg.2024.107997
  18. ↑ 刘进, 张文胜, 马海军, 王昌华, 解振彪. Substituted nitrogen heterocyclic compound and anesthetic effect thereof. Patent WO 2021/068943