6-Monoacetylmorphine (6-MAM, 6-acetylmorphine, or 6-AM) is one of three active

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of

heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a potent opioid mainly used as a recreational drug for its euphoric effects. Medical grade diamorphine is used as a pure hydrochloride salt. Various white and brow ...

(diacetylmorphine), the others being

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

and the much less active

3-monoacetylmorphine 3-Monoacetylmorphine (3-MAM) or 3-acetylmorphine is a less active metabolite of heroin (diacetylmorphine), the other two being morphine and more active 6-monoacetylmorphine 6-Monoacetylmorphine (6-MAM, 6-acetylmorphine, or 6-AM) is one of th ...

(3-MAM).

Pharmacology

6-MAM occurs as a metabolite of heroin. Once it has passed

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...

, 6-MAM is then metabolized into morphine or excreted in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

. Heroin is rapidly metabolized by

esterase An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis. A wide range of different esterases exist that differ in their substrate specificity, their protein structure, ...

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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

, serving as a lipophilic transporter for the systemic delivery of morphine, which actively binds with μ-opioid receptors. Heroin black tar

6-MAM already has a free 3-hydroxy group and shares the high

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...

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.

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 Black tar heroin is a form of heroin that is sticky like tar or hard like coal. Its dark color is the result of crude processing methods that leave behind impurities. Despite its name, black tar heroin can also be dark orange or dark brown in ap ...

along with heroin itself.

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 Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

with an

organic base An organic base is an organic compound which acts as a base. Organic bases are usually, but not always, proton acceptors. They usually contain nitrogen atoms, which can easily be protonated. For example, amines or nitrogen-containing heterocyclic ...

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 Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a col ...

, 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 vinegar.

Chemistry

Detection in bodily fluids

Since 6-MAM is a metabolite unique to heroin, its presence in the urine confirms heroin use. This is significant because a urine

immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...

drug screen typically tests for morphine, which is a metabolite of a number of legal and illegal opiates/opioids such as

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

, 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. 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 trace amounts in the brain of certain mammals.

References