Heterocodeine

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
Clinical data
Other namesHeterocodeine, 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
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.010.325
Chemical and physical data
FormulaC18H21NO3
Molar mass299.370 g·mol−1
3D model (JSmol)
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 Y
  • Key:FNAHUZTWOVOCTL-XSSYPUMDSA-N Y
 NY (what is this?)  (verify)

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
  1. US 2058521
  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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