Heterocodeine

Heterocodeine
Clinical data
Other names	Heterocodeine, Morphine 6-methyl ether
ATC code	none;
Legal status
Legal status	US: Schedule II;
Identifiers
	IUPAC name (5α,6α)-6-Methoxy-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3-ol;
CAS Number	639-47-4 ;
PubChem CID	5462505;
ChemSpider	4575432 ;
UNII	SBO5K94K8L;
ChEMBL	ChEMBL358043 ;
CompTox Dashboard (EPA)	DTXSID40905126 ;
ECHA InfoCard	100.010.325
Chemical and physical data
Formula	C18H21NO3
Molar mass	299.370 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O(C)[C@H]2\C=C/[C@H]5[C@@H]4N(CC[C@@]51c3c(O[C@H]12)c(O)ccc3C4)C;
	InChI InChI=1S/C18H21NO3/c1-19-8-7-18-11-4-6-14(21-2)17(18)22-16-13(20)5-3-10(15(16)18)9-12(11)19/h3-6,11-12,14,17,20H,7-9H2,1-2H3/t11-,12+,14-,17-,18-/m0/s1 ; Key:FNAHUZTWOVOCTL-XSSYPUMDSA-N ;
	(what is this?) (verify)

Heterocodeine (6-methoxymorphine) is an opiate derivative, the 6-methyl ether of morphine, and a structural isomer of codeine; it is called "hetero-" because it is the reverse isomer of codeine. Heterocodeine was first synthesised in 1932 and first patented in 1935.^[1] It can be made from morphine by selective methylation.^[2] Codeine is the natural mono-methyl ether, but must be metabolized for activity (that is, it is a prodrug). In contrast the semi-synthetic mono-methyl ether, heterocodeine is a direct agonist. The 6,7,8,14 tetradehydro 3,6 methyl di-ether of morphine is thebaine.

Heterocodeine is 6 times more potent than morphine^[3] due to having a substitution at the 6-hydroxy position, in a similar manner to 6-acetylmorphine.^[4] The drug methyldihydromorphine (dihydroheterocodeine) is a derivative of heterocodeine. Like the morphine metabolite morphine-6-glucuronide, 6-position branches (esters or ethers) of morphine bind to the otherwise unagonized human mu receptor subtype mu-3 (or μ3); as well as the 6-acetylmorphine metabolite of heroin this includes heterocodeine.^[5]

The relative strength of heterocodeine to codeine has been published as 50, 72, 81, 88, 93, 96, and 108 ×.

It is not mentioned specifically in the Controlled Substances Act 1970 but is a Schedule II controlled substance as an analogue of morphinan or morphine under the morphine structure rules of the Analogues Act; in other countries it is usually controlled as a strong opioid.

Homocodeine is a synonym for pholcodine. Bicodeine is a dimer of codeine which is essentially the codeine analogue of pseudomorphine and is also known as pseudocodeine. It is an occasional component of opium and is also a decomposition product of codeine under certain circumstances.^[6]

References

^ US 2058521
^ Barber RB, Rapoport H (November 1975). "Synthesis of thebaine and oripavine from codeine and morphine". Journal of Medicinal Chemistry. 18 (11): 1074–7. doi:10.1021/jm00245a006. PMID 1177252.
^ Woster PM. "Chemistry of Opioid Analgesics". PHA 5155- Neurology Pharmacotherapeutics Medicinal Chemistry Tutorials. Archived from the original on 2007-07-16.
^ Coop A, Jacobson AE (2000). "Biological evaluation of compounds for their physical dependence potential & abuse liability. XXIV" (PDF). Drug evaluation committee of the college on problems of drug dependence.
^ Brown GP, Yang K, King MA, Rossi GC, Leventhal L, Chang A, Pasternak GW (July 1997). "3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist". FEBS Letters. 412 (1): 35–8. doi:10.1016/S0014-5793(97)00710-2. PMID 9257684. S2CID 45475657.
^ "Status Decision of Controlled and Non-Controlled Substances: Codeine dimer" (PDF). Health Canada. 15 June 2005.

[1] US 2058521

[pmid1177252-2] Barber RB, Rapoport H (November 1975). "Synthesis of thebaine and oripavine from codeine and morphine". Journal of Medicinal Chemistry. 18 (11): 1074–7. doi:10.1021/jm00245a006. PMID 1177252.

[3] Woster PM. "Chemistry of Opioid Analgesics". PHA 5155- Neurology Pharmacotherapeutics Medicinal Chemistry Tutorials. Archived from the original on 2007-07-16.

[4] Coop A, Jacobson AE (2000). "Biological evaluation of compounds for their physical dependence potential & abuse liability. XXIV" (PDF). Drug evaluation committee of the college on problems of drug dependence.

[5] Brown GP, Yang K, King MA, Rossi GC, Leventhal L, Chang A, Pasternak GW (July 1997). "3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist". FEBS Letters. 412 (1): 35–8. doi:10.1016/S0014-5793(97)00710-2. PMID 9257684. S2CID 45475657.

[6] "Status Decision of Controlled and Non-Controlled Substances: Codeine dimer" (PDF). Health Canada. 15 June 2005.

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