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Etorphine
Clinical data
AHFS/Drugs.com	International Drug Names
ATCvet code	QN02AE90 (WHO) ;
Legal status
Legal status	AU: S9 (Prohibited substance); BR: Class F1 (Prohibited narcotics); CA: Schedule I; DE: Anlage III (Special prescription form required); UK: Class A; US: Schedule I and Schedule II; UN: Narcotic Schedules I and IV; EU: List I (Netherlands);
Identifiers
	IUPAC name (5α,6β,14β,18R)-18-[(2R)-2-Hydroxy-2-pentanyl]-6-methoxy-17-methyl-7,8-didehydro-18,19-dihydro-4,5-epoxy-6,14-ethenomorphinan-3-ol;
CAS Number	14521-96-1 ;
PubChem CID	644209;
IUPHAR/BPS	1625;
DrugBank	DB01497 ;
ChemSpider	559231 ;
UNII	42M2Y6NU9O;
KEGG	D07937 ;
ChEBI	CHEBI:4912 ;
ChEMBL	ChEMBL140050;
CompTox Dashboard (EPA)	DTXSID40878669 DTXSID40878667, DTXSID40878669 ;
ECHA InfoCard	100.035.017
Chemical and physical data
Formula	C25H33NO4
Molar mass	411.542 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@](CCC)(O)[C@H]1C[C@]23C=C[C@]1(OC)[C@@H]4Oc5c(O)ccc6C[C@H]2N(C)CC[C@]43c65;
	InChI InChI=1S/C25H33NO4/c1-5-8-22(2,28)17-14-23-9-10-25(17,29-4)21-24(23)11-12-26(3)18(23)13-15-6-7-16(27)20(30-21)19(15)24/h6-7,9-10,17-18,21,27-28H,5,8,11-14H2,1-4H3/t17-,18-,21-,22-,23-,24+,25-/m1/s1 ; Key:CAHCBJPUTCKATP-FAWZKKEFSA-N ;
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Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine.^[1] It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather the related plants Papaver orientale and Papaver bracteatum.^[2] It was reproduced in 1963 by a research group at MacFarlan Smith in Gorgie, Edinburgh, led by Kenneth Bentley.^[3] It can be produced from thebaine.^[4]

Veterinary use

Etorphine is available legally only for veterinary use and is strictly governed by law. It is often used to immobilize elephants and other large mammals. Diprenorphine (Revivon) is an opioid receptor antagonist that can be administered in proportion to the amount of etorphine used (1.3 times) to reverse its effects. Veterinary-strength etorphine is fatal to humans. For this reason the package as supplied to vets always includes the human antidote along with the etorphine.

The human antidote is generally naloxone, not diprenorphine, and is always prepared before the preparation of etorphine to be immediately administered following accidental human exposure to etorphine. The LD₅₀ in humans is 3 μg which led to the requirement that the medicine include an equal dose of an antidote, diprenorphine or naloxone.

One of its main advantages is its speed of operation, and more importantly, the speed that diprenorphine reverses its effects. The high incidence of side effects, including severe cardiopulmonary depression, has caused etorphine to fall into disfavor in general veterinary practice. However, its high potency, combined with the rapid action of both etorphine and its antagonist, diprenorphine, means that it has found a place for use in the capture of large mammals, such as rhinoceroses and elephants, where rapid onset and rapid recovery are both very important. The high potency of etorphine means that sufficient etorphine can be administered to large wild mammals by projectile syringe (dart).

Large Animal Immobilon is a combination of etorphine plus acepromazine maleate. An etorphine antidote Large Animal Revivon contains mainly diprenorphine for animals and a human-specific naloxone-based antidote, which should be prepared prior to the etorphine. A 5–15 mg dose is enough to immobilize an African elephant and a 2–4 mg dose is enough to immobilize a black rhinoceros.^[5]

Pharmacology

Etorphine is a potent, non-selective full agonist of the μ-, δ-, and κ-opioid receptors.^[6]^[7] It has a weak affinity for the nociceptin receptor.^[8] Etorphine has an LD₅₀ of 3 μg in humans.^[9]

Legal status

In Hong Kong, etorphine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.^[10]

In the Netherlands, etorphine is a Schedule I drug of the Opium Law. It is used only for veterinary purposes in zoos to immobilize large animals.^[11]

In the US, etorphine is listed as a Schedule I drug with an ACSCN of 9056, although its hydrochloride salt is classified as Schedule II with an ACSCN of 9059.^[12]

In the UK, under the Misuse of Drugs Act 1971, etorphine is controlled as a Class A substance.^[13]

In Italy, Etorphine is illegal, as are the parent compounds Dihydroetorphine and Acetorphine. (Datas from 2022)^[14]

In popular culture

The fictional character Dexter Morgan uses Etorphine M-99 to capture and sedate his victims in the TV shows Dexter, Dexter: New Blood, and Dexter: Original Sin.
The fictional character Dwight Schrute uses etorphine to sedate a coworker in the TV show The Office.

References

^ Bentley KW, Hardy DG (June 1967). "Novel analgesics and molecular rearrangements in the morphine-thebaine group. 3. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine". Journal of the American Chemical Society. 89 (13): 3281–3292. doi:10.1021/ja00989a032. PMID 6042764.
^ Aggrawal A (1995). "Chapter 3 Opium: the king of narcotics". Narcotic Drugs. New Delhi: National Book Trust. pp. xvi+161. ISBN 81-237-1383-5.
^ Bentley KW, Hardy DG (1963). "New potent analgesics in the morphine series". Proceedings of the Chemical Society. 220: 189–228. doi:10.1039/PS9630000189.
^ Huang XR, Srimurugan S, Lee GH, Chen C (February 2011). "A Facile Synthesis and Structural Verification of Etorphine and Dihydroetorphine from Codeine". Journal of the Chinese Chemical Society. 58 (1): 101–107. doi:10.1002/jccs.201190048. ISSN 0009-4536.
^ "Etorphine HCl". Veterinary medicine for wildlife: immobilisation medicine for animals zoo animals. Zoo Pharm. Archived from the original on 2016-09-08. Retrieved 2013-10-11.
^ Pasternak G (17 April 2013). The Opiate Receptors. Springer Science & Business Media. pp. 444–. ISBN 978-1-60761-990-1.
^ Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J (January 2006). "Pharmacological profiles of opioid ligands at kappa opioid receptors". BMC Pharmacology. 6 (1): 3. doi:10.1186/1471-2210-6-3. PMC 1403760. PMID 16433932.
^ Hawkinson JE, Acosta-Burruel M, Espitia SA (February 2000). "Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors". European Journal of Pharmacology. 389 (2–3): 107–114. doi:10.1016/S0014-2999(99)00904-8. PMID 10688973.
^ Riviere JE, Papich MG (2009-03-17). Riviere JE, Papich MG (eds.). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 32. ISBN 978-0-8138-2061-3.
^ "Hong Kong e-Legislation". www.elegislation.gov.hk. Retrieved 2022-03-30.
^ "Opiumwet". Ministerie van Binnenlandse Zaken en Koninkrijksrelaties (in Dutch). Retrieved 2022-03-30.
^ "Etorphine". PubChem. U.S. National Library of Medicine. CID 26721. Retrieved 2022-03-30.
^ "List of most commonly encountered drugs currently controlled under the misuse of drugs legislation". GOV.UK. Retrieved 2022-03-30.
^ "Tabelle delle sostanze stupefacenti e psicotrope". Ministero della Salute (in Italian). Retrieved 2022-04-09.