6-Monoacetylmorphine

6-Monoacetylmorphine

Clinical data
Routes of administration	Intravenous
ATC code	none
Legal status
Legal status	AU: S9 (Prohibited) UK: Class A US: Schedule I
Pharmacokinetic data
Biological half-life	< 5 mins
Identifiers
IUPAC name 3-hydroxy-6-acetyl-(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methylmorphinan
Synonyms	6-acetylmorphine
CAS Number	2784-73-8
PubChem (CID)	5462507
ChemSpider	4575434
ChEMBL	CHEMBL592009
Chemical and physical data
Formula	C19H21NO4
Molar mass	327.374 g/mol
3D model (Jmol)	Interactive image
SMILES CC(=O)c3cc(O)c1O[C@@H]4[C@]25CCN(C)[C@H](Cc3c12)[C@@H]5/C=C\[C@@H]4O
InChI InChI=1S/C19H21NO4/c1-9(21)10-8-15(23)17-16-11(10)7-13-12-3-4-14(22)18(24-17)19(12,16)5-6-20(13)2/h3-4,8,12-14,18,22-23H,5-7H2,1-2H3/t12-,13+,14-,18-,19-/m0/s1 Key:DUAISAINBBQDAF-LEPYJNQMSA-N
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6-Monoacetylmorphine (6-MAM) or 6-acetylmorphine (6-AM) is one of three active metabolites of heroin (diacetylmorphine), the others being morphine and the much less active 3-monoacetylmorphine (3-MAM).

Pharmacology

6-MAM occurs as a metabolite of heroin once it has passed first-pass metabolism. 6-MAM and then is metabolized into morphine or excreted in urine.

Heroin is rapidly metabolized by esterase enzymes in the brain and has an extremely short half-life. It has also relatively weak affinity to μ-opioid receptors because the 3-hydroxy group, essential for effective binding to the receptor, is masked by the acetyl group. Therefore, heroin acts as a pro-drug, serving as a lipophilic transporter for the systemic delivery of morphine, which actively binds with μ-opioid receptors.^[1][2]

Black tar heroin

6-MAM already has a free 3-hydroxy group and shares the high lipophilicity of heroin, so it penetrates the brain just as quickly and does not need to be deacetylated at the 6-position in order to be bioactivated; this makes 6-MAM somewhat more potent than heroin.^[3]

Availability

6-MAM is rarely encountered in an isolated form due to the difficulty in selectively acetylating morphine at the 6-position without also acetylating the 3-position. However, it is found in significant amounts in black tar heroin with diacetylmorphine.

Synthesis

The production of black tar heroin results in significant amounts of 6-MAM in the final product. 6-MAM is approximately 30 percent more active than diacetylmorphine itself, This is why despite lower heroin content, black tar heroin may be more potent than some other forms of heroin. 6-MAM can be synthesized from morphine using glacial acetic acid with an organic base as a catalyst. The acetic acid must be of a high purity (97-99 per cent) for the acid to properly acetylate the morphine at the 6th position effectively creating 6-MAM. Acetic acid is used rather than acetic anhydride, as acetic acid is not strong enough to acetylate the phenolic 3-hydroxy group but is able to acetylate the 6-hydroxy group, thus selectively producing 6-MAM rather than heroin. Acetic acid is a convenient way to produce 6-MAM, as acetic acid also is not a watched chemical as it is the main component of vinager.

Chemistry

Detection in bodily fluids

Since 6-MAM is a unique metabolite to heroin, its presence in the urine confirms that heroin was the opioid used. This is significant because on a urine immunoassay drug screen, the test typically tests for morphine, which is a metabolite of a number of legal and illegal opiates/opioids such as codeine, morphine sulfate, and heroin. Trace amounts of 6-MAM, a specific metabolite of heroin, are also excreted for approximately 6–8 hours following heroin use.^[4] so a urine specimen must be collected soon after the last heroin use, however, the presence of 6-MAM suggests that heroin was used as recently as within the last day. 6-MAM is naturally found in the brain of certain mammals.^[5]

See also

• M3G, morphine-3-glucuronide an inactive metabolite of morphine much as 3-MAM is the less active metabolite of heroin (notably here as morphine is an active secondary metabolite of heroin itself with 6-Monoacetylmorphine being the intermediate stage)
• M6G, morphine-6-glucuronide the active variant in close relation to 6-MAM, being relative as twin metabolites of this articles very metabolite itself, morphine, twinned to a metabolite (3-MAM) of a parent compound (heroin) of this article's chemical

Acetyl groups of heroin. In 6-MAM upper group is changed to hydrogen making hydroxyl-group in 3-position.

References

1. "Evidence from opiate binding studies that heroin acts through its metabolites". Life Sci. 33 Suppl 1: 773–6. 1983. doi:10.1016/0024-3205(83)90616-1. PMID 6319928.
2. Ricerca Italiana - PRIN - Role of morphine glucuronides in heroin addiction
3. "Relative cataleptic potency of narcotic analgesics, including 3,6-dibutanoylmorphine and 6-monoacetylmorphine". Prog. Neuropsychopharmacol. Biol. Psychiatry. 8 (4-6): 747–50. 1984. doi:10.1016/0278-5846(84)90051-4. PMID 6543399.
4. https://www.redwoodtoxicology.com/resources/drug_info/opiates
5. "6-Acetylmorphine: a natural product present in mammalian brain". Proc. Natl. Acad. Sci. U.S.A. 85 (14): 5335–8. July 1988. doi:10.1073/pnas.85.14.5335. PMC 281745. PMID 3393541.