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The ACMD’s Mephedrone Report Part II

By John Clarke

This post contains the important annexes from the ACMD’s report on mephedrone and related cathinones. You can read the main body of the report here: The ACMD’s Mephedrone Report Part I. The original pdf is linked to at the end of this post.

I’ll probably write a few comments about the entire report in my next post, whenever that may be. Anyhoo…

Annex A. Recommendation For The Generic Control Of The Cathinone Derivatives

Scope of a generic definition

The ACMD here set out recommendations on the range of compounds that should be included in a generic definition for the control of cathinone derivatives under the Misuse of Drugs Act 1971.

It was proposed that the scope of compounds covered by generic control should be much wider than the 6 ring substituted compounds listed in Table 1 (annex A) and wider than the 10 compounds reported to the EMCDDA since 2006.

The scope should include all cathinone derivatives that have been found in seizures and collected samples together with compounds that have not been encountered but have misuse potential. This includes cathinone derivatives with and without ring substituents and with side chains longer than those usually encountered in the phenethylamine drugs.

The scope should also include any substances known or believed to be pro-drugs, i.e. substances that are metabolised to a known active substance (for example GBL is converted in the body to GHB).

The generic definition should not include those substances already controlled under the Misuse of Drugs Act, i.e. diethylpropion (Class C), cathinone (Class C), methcathinone (Class B) and pyrovalerone (Class C). Finally the definition should not include any substances, e.g. bupropion, that are ingredients of legitimate pharmaceutical products or that have other legitimate uses.

The structure of cathinone derivatives is represented by the generalised structure below:

Figure 1: Generalised structure of cathinone derivatives
where,

R1= single alkyl group [but not H]
R2= H or alkyl
R3= H or alkyl or
[NR2R3] = pyrrolidino or phthalimido or other ring structure
R4= H (no substituents) or
= one or more of alkyl, alkoxy, alkylenedioxy and halide whether or
not further substituted with an other univalent substituent

The phthalimido group has so far only been encountered in the compound a-phthalimidopropiophenone. This substance has been found in a capsule in combination with 2-fluoromethcathinone and in capsules containing a mixture with 4-methylmethcathinone, N-ethylcathinone, and caffeine.

The reason for adding a-phthalimidopropiophenone is not clear. It may have been added deliberately, perhaps as a pro-drug for cathinone, but there is no information about its pharmacology or metabolism. This substance is also an intermediate in the synthesis of cathinone and N-alkyl derivatives of cathinone. It could therefore be present unintentionally as a residue of an intermediate, the product of a failed chemical synthesis, or even the miss-labelling of an intermediate.

In addition to compounds with the generalised structure in (Figure 1, Annex A) the phenyl ring can be replaced with a naphthyl ring (e.g. Figure 2, Annex A) or with a thiophene ring. The naphthyl analogue of pyrovalerone (Figure 2, Annex A) is available on the Internet and is being retailed as “NRG-1”. These compounds cannot easily be included in a generic definition for the cathinone derivatives having the generalised structure in Figure 1, Annex A, but they could be controlled as named substances or by one or more separate generic definitions. The ACMD intend to review these substances and provide further advice at a later date.

Figure 2: Naphthyl analogue of pyrovalerone

The systematic chemical name for the structure in Figure 2, Annex A is 1-(2-naphthyl)-2-(1-pyrrolidinyl)-1-pentanone and alternative names include naphthylpyrovalerone, naphyrone and O-2482.

Appendix I, of this Annex includes all the cathinone derivatives, with the general structure in Figure 1, Annex A, that have been encountered in seizures and collected samples, substances that are already controlled, ingredients of known pharmaceutical products, substances available via the Internet and substances that are listed in Wikipedia. However, the market for cathinone derivatives is still evolving and new substances will continue to appear.

Many cathinone derivatives are mentioned in patents for pharmaceutical applications but the only known non-controlled cathinone derivative with a marketing authorisation appears to be bupropion, an ingredient of ®Zyban.

Some cathinone derivatives are mentioned in patents for non-pharmaceutical applications.

A structure-based search of the 12th Edition of the Merck Index (1996), carried out previously by Dr Les King, found no contentious compounds.

Interestingly, a recent patent (WO PCT 2010006196) relating to water purification membranes mentions the compound in Figure 3 below, which is closely related to methylone (bk-MDMA). This compound would be included within a generic definition since the term methylenedioxy can have two meanings. However, compounds analogous to those in Figure 3, Annex A are unlikely to have any commercial uses.

Figure 3: 3,4-methylenedioxy-N-methyl-ß-keto-amphetamine

Structure Activity Relationships

Cathinone derivatives have a range of effects (e.g. stimulant, empathogen and antidepressant).

The cathinone derivatives without ring substituents (e.g. diethylpropion, methcathinone, buphedrone, N,N-dimethylcathinone) are mostly stimulants.

Most of the cathinone derivatives encountered as legal highs are ring substituted compounds with a secondary amino group (R2 = methyl or ethyl and R3 = hydrogen) or with a cyclic amino group (NR2R3 = pyrrolidino group or phthalimido group). These substances are primarily stimulants, with varying degrees of empathogenic effects (i.e. similar in effects to MDMA). Ring substituents (R4) have included alkyl, alkoxy, methylenedioxy and halide.

The side chain substituent (R1) has mostly been a single alkyl group. However there are examples with allyl (an alkenyl) and propargyl (an alkynyl) groups and also examples with a second alkyl group attached to the same carbon atom as R1, but these compounds are not within the proposed scope.

No haloalkyl substituents (e.g. trifluoromethyl –CF3 as found in piperazine derivatives) in the ring (R4) or on the side chain (R1) have been encountered or reported in the literature. However, replacement of the ring methyl group, as in mephredrone, with a trifluoromethyl group is likely to produce substances with similar activities. It is recommended therefore that haloalkyl substituents be included in the generic definition for ring substituents.

Cathinone derivatives with a primary amino group (i.e. no N-alkyl substituents) are rarely encountered, possibly because of their instability. There are only two known examples, bk-MDA (known to substitute for MDMA in rats) and cathinone (a stimulant).

The NR2R3 amino groups reported in the scientific literature have included alkylamino (R2 = alkyl, R3 = H), dialkylamino (R2 =alkyl, R3 = alkyl), the cyclic pyrrolidino group and a large number of other cyclic amines. However, for the pyrovalerone analogues an increase in size of the nitrogen containing ring from a five-membered pyrrolidine ring to a six-membered piperidine ring resulted in a substantial loss in binding potency. There are also examples of N-allyl, N-propargyl and N-cycloalkyl substituents.

The anti-depressant drug bupropion has a tertiary-butyl group on the nitrogen atom and several other substances investigated for their potential as smoking cessation drugs also have a bulky alkyl group on the nitrogen atom, e.g. tertiary-butyl, iso-propyl or cycloalkyl, or the alkyl amino group is replaced by a cyclic piperidino group (a cyclic amino group with 6 membered ring).

Salts, stereoisomers, esters and ethers

Cathinone derivatives with the generalised structure in Figure 1, Annex A, all have an asymmetric a-carbon atom giving rise to R and S stereoisomers.

With the exception of the phthalimido derivatives, all cathinone derivatives have a basic nitrogen atom and can therefore form salts.

There is no definition of esters and ethers in the Misuse of Drugs Act 1971, but from a chemical perspective esters usually only applies to derivatives of acids with a hydroxyl group, and derivatives of alcohols and phenols. Likewise ethers usually only applies to derivatives of alcohols and phenols. On this basis the cathinone derivatives would not form esters or ethers.

However, keto compounds, R1R2C=O, can form ketals, R1R2C(OR’)2, which arguably might be described as a special form of an ether. Ketals of cathinone derivatives have been discussed on drug forums in the context of a pro-drug and are mentioned in the scientific literature, usually as a means of protecting the keto group during chemical syntheses.

Generic definition for the control of cathinone derivatives

The ACMD have considered a number of options for the control of cathinone derivatives, including listing of named substances, several generic definitions and combinations of these approaches.

Taking into account the ACMD’s consideration of the scope, together with structure activity relationships and prevalence of known cathinone derivatives, the following generic definition is recommended:

Any compound (not being bupropion or a substance for the time being specified in paragraph 2.2) structurally derived from 2-amino-1-phenyl-1-propanone by modification in any of the following ways, that is to say,

  1. by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents;
  2. by substitution at the 3-position with an alkyl substituent;
  3. by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure.

Notes

  • the parent compound is cathinone
  • “any” is taken to mean one or more

Comments

This is a definition that includes all permutations for the three substitution areas, i.e. in the ring (R4), in the side chain (R1) and on the nitrogen (NR2R3).

  • All the cathinone derivatives would be in the same Class which would result in some anomalies for compounds already controlled.
  • Includes all the compounds in Appendix 1.
  • Includes primary amines without ring substituents (no known examples, except cathinone which is not included within the scope of this definition).
  • Includes ring substituted primary amines (bk-MDA is the only example).
  • The term “cyclic structure” has a very wide scope (e.g. all ring sizes, all heterocyclic nitrogen compounds and structures with ring substituents).

Appendix 1

Cathinone
(Class C)
beta-keto-amphetamine

Note: only encountered in Khat although it has been encountered as the pro-drug, a-phthalimidopropiophenone (see below)

R1 = Me
R2 = H
R3 = H
R4 = H
Cathinone
a-phthalimidopropiophenone

Note: found in products from the Internet

R1 = Me
NR2R3 = phthalimide
R4 = H
a-phthalimidopropiophenone
Methcathinone
(Class B)
Ephedrone
a-methylaminopropiophenone
R1 = Me
R2 = Me
R3 = H
R4 = H
Methcathinone
N,N-Dimethylcathinone
Metamfepramone
Dimethylpropion

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = Me
R4 = H
N,N-Dimethylcathinone
Ethcathinone
Ethylpropion
N-ethylcathinone
2-ethylamino-propiophenone
Sub Coca II

Note: encountered in seizures

R1 = Me
R2 = Et
R3 = H
R4 = H
Ethcathinone
Diethylpropion
(Class C)
Diethylcathinone
Amfepramone
R1 = Me
R2 = Et
R3 = Et
R4 = H
Diethylpropion
a-Pyrrolidinopropiophenone
a-PPP

Note: encountered in Germany

R1 = Me
NR2R3 = Pyrrolidinyl
R4 = H
a-Pyrrolidinopropiophenone
Buphedrone
2-methylamino-1-phenylbutan-1-one

Note: no seizures reported to EMCDDA but is available via the Internet and user reports are on drug forums.

R1 = Et
R2 = Me
R3 = H
R4 = H
Buphedrone
a-Pyrrolidinobutiophenone
a-PBP

Note: no seizure or user reports but listed on Wikipedia and in a patent

R1 = Et
NR2R3 = Pyrrolidinyl
R4 = H
a-Pyrrolidinobutiophenone
a-Pyrrolidinovalerophenone
a-PVP
a-Pyrrolidinopentiophenone

Note: No seizures reported to EMCDDA, but metabolism study by Germany, as a result of 2 seizures, in Germany and Netherlands.

R1 = n-Pr
NR2R3 = Pyrrolidinyl
R4 = H
a-Pyrrolidinovalerophenone
Mephedrone
4-Methylmethcathinone
4-MMC
Sub Coca I

Note: most frequently encountered cathinone derivative

R1 = Me
R2 = Me
R3 = H
R4 = 4-Me
Mephedrone
4’-methyl-a-pyrrolidinopropiophenone
MPPP

Note: seizure report from Germany

R1 = Me
NR2R3 = Pyrrolidinyl
R4 = 4-Me
4’-methyl-a-pyrrolidinopropiophenone
4’-methyl-a-pyrrolidinobutiophenone
MPBP

Note: seizure report from Germany

R1 = Et
NR2R3 = Pyrrolidinyl
R4 = 4-Me
4’-methyl-a-pyrrolidinobutiophenone
Pyrovalerone
(Class C)
R1 = n-Pr
NR2R3 = Pyrrolidinyl
R4 = Me
Pyrovalerone
4’-methyl-a-pyrrolidinohexiophenone
MPHP

Note: seizure report from Germany

R1 = n-Bu
NR2R3 = Pyrrolidinyl
R4 = Me
4’-methyl-a-pyrrolidinohexiophenone
Methedrone
4-methoxymethcathinone
PMMC
bk-PMMA

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = H
R4 = 4-MeO
Methedrone
4’-Methoxy-a-pyrrolidinopropiophenone
MOPPP

Note: seizure report from Germany

R1 = Me
NR2R3 = Pyrrolidinyl
R4 = 4-MeO
Bupropion
(Zyban – medicinal product in UK)

Note: To be excluded from control. No reports of abuse)

R1 = Me
R2 = t-Bu
R3 = H
R4 = 3-Cl
Bupropion
Flephedrone
4-Fluoromethcathinone
4FMC

Note: encountered in seizures. The 3-fluoro and 2-fluoro isomers have also been found in products from the Internet.

R1 = Me
R2 = Me
R3 = H
R4 = 4-F
(also 2-F and 3-F)
Flephedrone
Methylone
3,4-Methylenedioxymethcathinone
bk-MDMA

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Methylone
Ethylone
3,4-methylenedioxyethcathinine
bk-MDEA

Note: encountered in seizures

R1 = Me
R2 = Et
R3 = H
R4 = 3,4-methylenedioxy
Ethylone
3’,4’-methylenedioxy-a-pyrrolidinopropiophenone
MDPPP

Note: seizure reports from Germany and Denmark

R1 = Me
NR2R3 = Pyrrolidinyl
R4 = 3,4-methylenedioxy
3’,4’-methylenedioxy-a-pyrrolidinopropiophenone
Butylone
ß-keto-N-methyl-3,4-benzodioxyolylbutanamine
bk-MDBD

Note: seizure reports from 7 countries

R1 = Et
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Butylone
3’,4’-Methylenedioxy-a-pyrrolidinobutiophenone

Note: no seizure reports, but mentioned in Wikipedia and in patent

R1 = Et
NR2R3 = Pyrrolidinyl
R4 = 3,4-methylenedioxy
3’,4’-Methylenedioxy-a-pyrrolidinobutiophenone
Pentylone
ß-Keto-methylbenzodioxolylpentanamine
bk-Methyl-K
bk-MBDP

Note: no seizure reports, but mentioned in Wikipedia and in patent.

R1 = n-Pr
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Pentylone
Methylenedioxypyrovalerone
MDPV

Note: encountered in seizures

R1 = n-Pr
NR2R3 = Pyrrolidinyl
R4 = 3,4-methylenedioxy
Methylenedioxypyrovalerone

Annex B & C

…Aren’t really worth including here. They contain a list of ACMD members and a list of organisations and individuals who submitted evidence included in the report. Go and read it in the original pdf if you want to. Go on! Go and bloody read it!

Annex D. Letter From The Advisory Council On The Misuse Of Drugs To The Home Secretary

22nd December 2009

Dear Home Secretary,

Re: ACMD consideration of mephedrone (and related cathinones)

The ACMD wrote to you in March to explain that it would be pleased to accede to the Government’s priorities that your predecessor set out in her letter of 13 March 2009. Concerning the issue of ‘legal highs’ the ACMD has provided advice on the synthetic cannabinoid receptor agonists (Spice), 1-benzylpiperazine, GBL and 1,4-BD all of which we note will be controlled in the legislation on the 23rd December. In the ACMD’s letter of 30 September 2009 it was explained that we would next provide you with advice on the cathinones.

Despite the difficulties of the last 2 months the ACMD is committed to providing you with advice on the cathinones. Although attention has focused on mephedrone, five other synthetic psychoactive cathinone derivatives are also widely available. The ACMD explained in a previous letter to you that it has concerns about the apparent prevalence and potential harms of these compounds. Much has been made of these compounds in the media over recent weeks; we find it of concern that this may have had the consequence of bringing such drugs to the attention of a wider demographic sooner than may have been the case.

The ACMD understand that mephedrone, amongst other cathinones, is being marketed as a variety of apparently ‘benign’ products e.g. bath salts or plant food. Whilst the potential harms of these drugs are not yet fully known, it is apparent that the selling of such unregulated preparations in a form that they are clearly unintended for could have serious public health implications.

The ACMD is mindful that, after recent events, our statutory membership requirements need to be fulfilled before providing formal advice, according to the requirements of the Misuse of Drugs Act 1971. However, the ACMD would like to assure you that it will seek to provide you with such advice at the earliest possible opportunity on this important issue.

I would be willing to discuss the issue of the cathinones and, more broadly, new psychoactive substances (‘legal highs’) and the timing of advice with you.

Yours sincerely,

Professor Les Iversen
(on behalf of the ACMD)

***

The original (boringly formatted) report can be found here: ACMD-cathinones-report.pdf.

2 Responses to The ACMD’s Mephedrone Report Part II

  1. Sharon says:

    you twa are something special. My keyboared is very stiicky, ent any comment further.

    I

  2. Steve Chapman says:

    Informative, beautifully illustrated and a joy to read. Having read the original report, this is an inspiring example of vastly improved, elegant information design. Well done.

    May I link to this page from my site?

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