Heterocodeine

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 461087666

| IUPAC_name = (5α,6α)-6-Methoxy-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3-ol

| image = Heterocodeine.svg

| alt = Skeletal formula

| width = 210

| image2 = Heterocodeine molecule ball.png

| alt2 = Ball-and-stick model

| tradename =

| pregnancy_AU =

| pregnancy_US =

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| legal_UK =

| legal_US = Schedule II

| legal_status =

| routes_of_administration =

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 639-47-4

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = SBO5K94K8L

| ATC_prefix = none

| ATC_suffix =

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 358043

| PubChem = 5462505

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4575432

| C=18 | H=21 | N=1 | O=3

| 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

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = FNAHUZTWOVOCTL-XSSYPUMDSA-N

| synonyms = Heterocodeine, Morphine 6-methyl ether

}}

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.{{cite patent | country = US | number = 2058521 }} It can be made from morphine by selective methylation.{{cite journal | vauthors = Barber RB, Rapoport H | title = Synthesis of thebaine and oripavine from codeine and morphine | journal = Journal of Medicinal Chemistry | volume = 18 | issue = 11 | pages = 1074–7 | date = November 1975 | pmid = 1177252 | doi = 10.1021/jm00245a006 }} 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{{cite web | title = Chemistry of Opioid Analgesics | work = PHA 5155- Neurology Pharmacotherapeutics Medicinal Chemistry Tutorials | vauthors = Woster PM | url = http://www.acsmedchem.org/module/opioid.html | archive-url = https://web.archive.org/web/20070716115228/http://www.acsmedchem.org/module/opioid.html | archive-date=2007-07-16 }} due to having a substitution at the 6-hydroxy position, in a similar manner to 6-acetylmorphine.{{cite web | url = http://www.pharmacy.umaryland.edu/faculty/acoop/decfolder/DEC2000.pdf | title = Biological evaluation of compounds for their physical dependence potential & abuse liability. XXIV. | work = Drug evaluation committee of the college on problems of drug dependence | date = 2000 | vauthors = Coop A, Jacobson AE }} 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.{{cite journal | vauthors = Brown GP, Yang K, King MA, Rossi GC, Leventhal L, Chang A, Pasternak GW | title = 3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist | journal = FEBS Letters | volume = 412 | issue = 1 | pages = 35–8 | date = July 1997 | pmid = 9257684 | doi = 10.1016/S0014-5793(97)00710-2 | s2cid = 45475657 | doi-access = free }}

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.{{cite web | title = Status Decision of Controlled and Non-Controlled Substances: Codeine dimer | work = Health Canada | date = 15 June 2005 | url = https://isomerdesign.com/Cdsa/HC/StatusDecisions/A-2013-00235%20-%20PDFs/C-Codeine%20dimer%202005-06-16.pdf}}