Methylecgonidine (anhydromethylecgonine; anhydroecgonine methyl ester; AEME) is a chemical intermediate derived from ecgonine or

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

. Methylecgonidine is a

pyrolysis The pyrolysis (or devolatilization) process is the thermal decomposition of materials at elevated temperatures, often in an inert atmosphere. It involves a change of chemical composition. The word is coined from the Greek-derived elements '' ...

product formed when

crack cocaine Crack cocaine, commonly known simply as crack, and also known as rock, is a free base form of the stimulant cocaine that can be smoked. Crack offers a short, intense high to smokers. The ''Manual of Adolescent Substance Abuse Treatment'' calls ...

is smoked, making this substance a useful biomarker to specifically test for use of crack cocaine, as opposed to powder cocaine which does not form methylecgonidine as a

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, ...

. Methylecgonidine has a relatively short half-life of 18–21 minutes, after which it is metabolised to

ecgonidine Ecgonidine (anhydroecgonine) is an alkaloid related to ecgonine and cocaine. It has a structure with a cycloheptene ring, with a nitrogen bridge, and a carboxylic acid side chain. Methylecgonidine is produced by pyrolysis in the process of smo ...

, meaning that the relative concentrations of the two compounds can be used to estimate how recently crack cocaine has been smoked. Methylecgonidine has been shown to be specifically more harmful to the body than other byproducts of cocaine; for example to the heart, lungs & liver. The toxicity is due to a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

effect at M1 and

M3 muscarinic receptors The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3. The M3 muscarinic receptors are located at many places in t ...

, leading to

DNA fragmentation DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually a ...

and neuronal death by

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

. AEME is also used in scientific research for the manufacture of

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...

analogues such as

troparil Troparil (also known as (–)-2β-Carbomethoxy-3β-phenyltropane, WIN 35,065-2, or β-CPT) is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine ...

, dichloropane, iometopane, and CFT. Methylecgonidine could also theoretically be used to produce

and so may be a

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...

in some countries.

Synthesis

Methylecgonidine can be synthesized non pyrolytically from cocaine via

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

followed by

esterification In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

with methanol. Methylecgonidine synthesis 2

The scheme by Kline is based on the reaction of 2,4,6-cycloheptatriene-7-carboxylic acid with methylamine. This is a modified version of by Grundmann and Ottmann. In the accompanying patent these same authors react their methylecgonidine with two equivalents of PhLi to form a tertiary alcohol by "hard" addition to the ester and not "soft" Michael addition. However, the product is only one tenth the potency of

atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given ...

. The methyl 2,4,6-cycloheptatriene-1-carboxylate can be made synthetically. Methylecgonidine synthesis 3

Davies ''et al.'' synthesized (''R''/''S'')-methylecgonidine by a tandem cyclopropanation/ Cope rearrangement. Thus, reaction of methyldiazobutenoate (2) with 5 equiv of ''N''-((2-(TMS)ethoxy)carbonyl)pyrrole (1) in the presence of rhodium(II) hexanoate/hexane gave the .2.1azabicyclic system (''R''/''S'')-8 in 62% yield. The unsubstituted double bond was selectively reduced using Wilkinson catalyst to provide N-protected anhydroecgonine methyl ester ((''R''/''S'')-4). Following deprotection of N8 nitrogen with

TBAF Tetra-''n''-butylammonium fluoride, commonly abbreviated to TBAF and ''n''-Bu4NF, is a quaternary ammonium salt with the chemical formula (CH3CH2CH2CH2)4N+F−. It is commercially available as the white solid trihydrate and as a solution in tet ...

and reductive methylation with formaldehyde and sodium cyanoborohydride, (''R''/''S'')-5 was obtained in overall good yield.

References

{{Reflist Tropane alkaloids Carboxylic acids Cycloalkenes

Synthesis

See also

References