To combat the illicit synthetic cannabinoid industry many jurisdictions have created a system to control these cannabinoids through their general (or Markush) structure as opposed to their specific identity. In this way new analogs are already controlled before they are even created.[1][2] A large number of cannabinoids have been grouped into classes based on similarities in their chemical structure, and these classes have been widely adopted across a variety of jurisdictions.[3][4][5][6][7][8]
Typical groups of compounds included for control may include naphthoylindoles, phenylacetylindoles, benzoylindoles, cyclohexylphenols, naphthylmethylindoles, naphthoylpyrroles, naphthylmethylindenes, indole-3-carboxamides, indole-3-carboxylates, indazole-3-carboxamides and sometimes others, each with specific substitutions on specific atoms of the molecule.[9] The scope of definitions and the range of compounds included may vary substantially between jurisdictions, so compounds which are legal in one country or state may be illegal in another.[10]
For example, in many jurisdictions there is a general control on Naphthoylindoles: "Any compound containing a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent." (example definition from Kentucky, which is substantially derived from the 2009 ACMD advice on synthetic cannabinoids in the UK)[11][12] This causes a substance such as MAM-2201 to be controlled as a Schedule 1 illegal drug, even though "MAM-2201" or its corresponding chemical name are not specifically listed in the statute.
MAM-2201
In the five carbon chain, the fluorine atom is attached to the nitrogen atom. A fluoropentyl chain falls within the scope of "haloalkyl" substitutions, and so with a methyl group attached to the carbon atom at the 4-position of the naphthyl ring (i.e. "substituted in the naphthyl ring to any extent"), and a fluoropentyl group attached to the nitrogen atom ("with substitution at the nitrogen atom of the indole ring by [a]...haloalkyl...group"), this compound falls within the scope of the general definition. It is in this way MAM-2201 can be controlled without being specifically named in the statute. On the other hand, THJ-2201 with an indazole core, falls outside this general definition, as it is a naphthoylindazole rather than a naphthoylindole. Note however that THJ-2201 is now specifically listed under US federal law.
Common examples of general controls
Naphthoylindoles: Any compound containing a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.[11]
Naphthoylindoles, where R, R1 and R2 are as defined in the statute
One specific example given is JWH-018, one of the earliest synthetic cannabinoids identified. Notice the indole ring has an alkyl substitution on the nitrogen atom, but there are no additional substitutions elsewhere on the molecule.
Phenylacetylindoles: Any compound containing a 3-phenylacetylindole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl,1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not further substituted in the indole ring to any extent and whether or not substituted in the phenyl ring to any extent.[13]
Phenylacetylindoles, where R, R1 and R2 are as defined in the statute
One example given is JWH-250. There is an alkyl substitution on the nitrogen atom of the indole ring as well as a methoxy group attached to the phenyl ring.
Benzoylindoles: Any compound containing a 3-(benzoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not further substituted in the indole ring to any extent and whether or not substituted in the phenyl ring to any extent.[14]
Benzoylindoles, where R, R1 and R2 are as defined in the statute
One example is RCS-4. Note the alkyl group substitution on the nitrogen atom of the indole. It is further substituted in the phenyl ring with a methoxy group.
Cyclohexylphenols: Any compound containing a 2-(3-hydroxycyclohexyl)phenol structure with substitution at the 5-position of the phenolic ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not substituted in the cyclohexyl ring to any extent.[15]
Cyclohexylphenols, where R and R1 are as defined in the statute
One example is CP 47,497. Notice the methyloctan-2-yl alkyl group substituted onto the 5-position of the phenol ring of the molecule. Note that this definition encompasses only those compounds that have OH groups attached to both the phenyl and the cyclohexyl rings, and so does not include compounds such as O-1871 which lacks the cyclohexyl OH group, or compounds such as JWH-337 or JWH-344 which lack the phenolic OH group. Some jurisdictions have addressed this by naming such compounds specifically, alternatively some have adopted broader definitions (such as in the Australian Federal Poisons Standard, which controls all derivatives of cyclohexylphenol unless otherwise specified).[16]
Naphthylmethylindoles: Any compound containing a 1H-indol-3-yl-(1-naphthyl)methane structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent.[17]
Naphthylmethylindoles, where R, R1 and R2 are as defined in the statute
One example is JWH-175. Notice the pentyl group substituted onto the nitrogen atom of the indole ring.
Naphthoylpyrroles: Any compound containing a 3-(1-naphthoyl)pyrrole structure with substitution at the nitrogen atom of the pyrrole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not further substituted in the pyrrole ring to any extent and whether or not substituted in the naphthyl ring to any extent.[18]
Naphthoylpyrroles, where R, R1 and R2 are as defined in the statute
One example is JWH-030. Notice the pentyl group on the nitrogen atom of the pyrrole ring of the molecule.
Naphthylmethylindenes: Any compound containing a 1-(1-naphthylmethyl)indene structure with substitution at the 3-position of the indene ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group whether or not further substituted in the indene ring to any extent and whether or not substituted in the naphthyl ring to any extent.[19]
"Naphthylmethylindenes" (sic), where R, R1 and R2 are as defined in the statute
One example is JWH-176. Notice the 5 membered pentyl chain on the 3-position of the indene ring. Strictly speaking this chemical name is incorrect, as JWH-176 and related compounds would more correctly be viewed as derivatives of 1-(1-naphthylmethylylidene)indene due to the unsaturated =CH- linker group (as opposed to the -CH2- linker group found in e.g. naphthylmethylindoles), however "Naphthylmethylindenes" has gained acceptance as a legal term of art in this instance.
JWH-176
Tetramethylcyclopropanoylindoles: Any compound containing a 3-(1-tetramethylcyclopropoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl, or 2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not further substituted in the tetramethylcyclopropyl ring to any extent.[20] While all known examples of compounds from this group have a 2,2,3,3-tetramethylcyclopropyl substituent, this definition would also encompass other isomers.
Tetramethylcyclopropanoylindoles, where R, R1 and R2 are as defined in the statute
One example is XLR-11. Notice the 5 membered alkyl group ending with a fluorine atom substituted onto the nitrogen atom of the indole group.
Adamantoylindoles: Any compound containing a 3-(1-adamantoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1-(N-methyl-2-piperidinyl)methyl,or2-(4-morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the adamantyl ring system to any extent.[21] Note that this definition (from the Kentucky statute) covers only compounds where the adamantyl group is attached by the 1-position, and would not include compounds where it is attached by the 2-position. Some other jurisdictions have consequently omitted the numbering from their corresponding definition (cf. Arizona for example), so as to cover a broader range of compounds.
Adamantoylindoles, where R, R1 and R2 are as defined in the statute
One example is AB-001. Notice the 5-membered alkyl group on the nitrogen atom of the indole ring.
Indole-3-carboxylate esters: Any compound containing a 1H-indole-3-carboxylate ester structure with the ester oxygen bearing a napthyl, quinolinyl, isoquinolinyl, or adamantyl group and substitution at the one position of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, benzyl, N-methyl-2-piperidinylmethyl, or 2-(4-morpholinyl)ethyl group, whether or not further substituted on the indole ring to any extent and whether or not further substituted on the naphthyl, quinolinyl, isoquinolinyl, adamantyl, or benzyl groups to any extent.[22]
Indole-3-carboxylate esters, where R, R1 and R2 are as defined in the statute
One example is PB-22. Notice the quinolinyl group attached to the oxygen atom and the 5 carbon chain (pentyl) group on the nitrogen atom.
Indazole-3-carboxamides: Any compound containing a 1H-indazole-3-carboxamide structure with substitution at the nitrogen of the carboxamide by a naphthyl, quinolinyl, isoquinolinyl, adamantyl, or 1-amino-1-oxoalkan-2-yl group and substitution at the one position of the indazole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, benzyl, N-methyl-2-piperidinylmethyl, or 2-(4-morpholinyl)ethyl group, whether or not further substituted on the indazole ring to any extent and whether or not further substituted on the naphthyl, quinolinyl, isoquinolinyl, adamantyl, 1-amino-oxoalkan-2-yl, or benzyl groups to any extent.[23]
Indazole-3-carboxamides, where R, R1 and R2 are as defined in the statute
One example is AB-CHMINACA. Notice the indazole group has a cyclohexylmethyl (a type of cycloalkylmethyl) group attached at the nitrogen atom. Also there is an 1-amino-1-oxoalkan-2-yl group (1-amino-3-methyl-1-oxobutan-2-yl in this instance) substituted on the nitrogen atom of the carboxamide group.
Other approaches to general controls
One consequence of the introduction of broad Markush structure bans, has been the appearance of compounds which have similar structures but technically fall outside the scope of the legal definitions (for instance containing an indazole core instead of the proscribed indole, or a carboxamide linker in place of methanone), therefore resulting over time in a progressively increasing structural diversity of synthetic cannabinoids sold for illicit recreational use.[24][25][26][27]
Some jurisdictions have attempted to introduce a broader scope of coverage by defining "head", "core", "linker" and "tail" groups which can be interchanged in any combination that fits within the definition, resulting in a much wider (but still usually finite) range of compounds being encompassed.[28]
Overview of the "head-core-tail" model of main group of synthetic cannabinoids
For example, the wording of this Texas statute encompasses a large range of "prophetic" core structures which have not yet been encountered in synthetic cannabinoids, but might plausibly be likely to appear in future (e.g. "Quinolinoyl pyrazole carboxylate", "Naphthoylimidazole" etc);
...(5) any compound containing a core component substituted at the 1-position to any extent, and substituted at the 3-position with a link component attached to a group A component, whether or not the core component or group A component are further substituted to any extent"[29]
Another approach (here from the UK) is to list an example structure and then specify ways in which it can be modified by swapping various parts of the molecule with alternative substituent groups, for example;
"...any compound (not being clonitazene, etonitazene, acemetacin, atorvastatin, bazedoxifene, indometacin, losartan, olmesartan, proglumetacin, telmisartan, viminol, zafirlukast or a compound for the time being specified in sub-paragraphs (h) to (s) above) structurally related to 1-pentyl-3-(1-naphthoyl)indole (JWH-018), in that the four sub-structures, that is to say the indole ring, the pentyl substituent, the methanone linking group and the naphthyl ring, are linked together in a similar manner, whether or not any of the sub-structures have been modified, and whether or not substituted in any of the linked sub-structures with one or more univalent substituents and, where any of the sub-structures have been modified, the modifications of the sub-structures are limited to any of the following, that is to say -
replacement of the indole ring with indane, indene, indazole, pyrrole, pyrazole, imidazole, benzimidazole, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine or pyrazolo[3,4-b]pyridine;
replacement of the pentyl substituent with alkyl, alkenyl, benzyl, cycloalkylmethyl, cycloalkylethyl, (N-methylpiperidin-2-yl)methyl, 2-(4-morpholinyl)ethyl or (tetrahydropyran-4-yl)methyl;
replacement of the methanone linking group with an ethanone, carboxamide, carboxylate, methylene bridge or methine group;
replacement of the 1-naphthyl ring with 2-naphthyl, phenyl, benzyl, adamantyl, cycloalkyl, cycloalkylmethyl, cycloalkylethyl, bicyclo[2.2.1]heptanyl, 1,2,3,4-tetrahydronaphthyl, quinolinyl, isoquinolinyl, 1-amino-1-oxopropan-2-yl, 1-hydroxy-1-oxopropan-2-yl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl or piperazinyl."[30]
Broadly worded controls such as above may inadvertently include large numbers of compounds which merely happen to have some structural similarity, but do not have similar pharmacological effects to the prohibited cannabinoid drugs. One approach to this is to specifically list examples of such compounds that need to be exempted from the general control, so that commonly used medicines do not become subject to control as illegal drug analogs.[31] Another issue is that even with such a wide range of structural modifications covered, modern predictive drug discovery techniques may generate novel analogues which still fall outside the specified range of prohibited structures.[32]
The Controlled Drugs and Substances Act is Canada's federal drug control statute. Passed in 1996 under Prime Minister Jean Chrétien's government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drugs Act, and establishes eight Schedules of controlled substances and two Classes of precursors. It provides that "The Governor in Council may, by order, amend any of Schedules I to VIII by adding to them or deleting from them any item or portion of an item, where the Governor in Council deems the amendment to be necessary in the public interest."
JWH-176 is an analgesic drug which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is 26.0 nM, making it more potent than THC itself, however JWH-176 is particularly notable in that it is a hydrocarbon containing no heteroatoms. This demonstrates that reasonably high-affinity cannabinoid binding and agonist effects can be produced by compounds with no hydrogen bonding capacity at all, relying merely on Van der Waals and possibly hydrophobic interactions to bind to the receptor. It was discovered by, and named after, John W. Huffman.
These drugs are known in the UK as controlled drug, because this is the term by which the act itself refers to them. In more general terms, however, many of these drugs are also controlled by the Medicines Act 1968, there are many other drugs which are controlled by the Medicines Act but not by the Misuse of Drugs Act, and some other drugs are controlled by other laws.
Substituted cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions. Cathinone occurs naturally in the plant khat whose leaves are chewed as a recreational drug.
JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was first reported in 1994 by a group including the noted cannabinoid chemist John W. Huffman. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), JWH-200 (WIN 55,225) and WIN 55,212-2 by the Sterling Winthrop group. Several other N-alkyl substituents were found to be active by Huffman's team including the n-butyl, n-hexyl, 2-heptyl, and cyclohexylethyl groups, but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead. Consequently, the 2-desmethyl derivative of JWH-007, JWH-018, has slightly higher binding affinity for CB1, with an optimum binding of 9.00 nM at CB1 and 2.94 nM at CB2, and JWH-007 displayed optimum binding of 9.50 nM at CB1 and 2.94 nM at CB2.
Cannabicyclohexanol is a cannabinoid receptor agonist drug, developed by Pfizer in 1979. On 19 January 2009, the University of Freiburg in Germany announced that an analog of CP 47,497 was the main active ingredient in the herbal incense product Spice, specifically the 1,1-dimethyloctyl homologue of CP 47,497, which is now known as cannabicyclohexanol. The 1,1-dimethyloctyl homologue of CP 47,497 is in fact several times more potent than the parent compound, which is somewhat unexpected as the 1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.
JWH-164 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It has approximately equal affinity for the CB1 and CB2 receptors, with a Ki of 6.6 nM at CB1 and 6.9 nM at CB2. JWH-164 is a positional isomer of the related compound JWH-081, but with a methoxy group at the 7-position of the naphthyl ring, rather than the 4-position as in JWH-081. Its potency is intermediate between that of JWH-081 and its ring unsubstituted derivative JWH-018, demonstrating that substitution of the naphthyl 7-position can also result in increased cannabinoid receptor binding affinity.
JWH-098 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It is the indole 2-methyl derivative of a closely related compound JWH-081, but has markedly different affinity for the CB1 and CB2 receptors. While JWH-081 is around tenfold selective for CB1 over CB2, in JWH-098 this is reversed, and it is around four times weaker than JWH-081 at CB1 while being six times more potent at CB2, giving it a slight selectivity for CB2 overall. This makes JWH-098 a good example of how methylation of the indole 2-position in the naphthoylindole series tends to increase CB2 affinity, but often at the expense of CB1 binding.
HU-243 (AM-4056) is a synthetic cannabinoid drug that is a single enantiomer of the hydrogenated derivative of the commonly used reference agonist HU-210. It is a methylene homologue of canbisol. It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.041 nM at the CB1 receptor, making it marginally more potent than HU-210, which had an affinity of 0.061 nM in the same assay.
JWH-175 is a drug from the naphthylmethylindole family which acts as a cannabinoid receptor agonist. It was invented by the scientist John W. Huffman and colleagues at Clemson University. JWH-175 is closely related to the widely used cannabinoid designer drug JWH-018, but with the ketone bridge replaced by a simpler methylene bridge. It is several times weaker than JWH-018, having a binding affinity at the CB1 receptor of 22 nM, though some derivatives substituted at the 4-position of the naphthyl ring have potency more closely approaching that of the equivalent naphthoylindoles. This makes JWH-175 considerably less potent than most synthetic cannabinoid drugs used in synthetic cannabis blends, and it is unclear if JWH-175 has ever been used for this purpose. However it has still been explicitly banned in several jurisdictions including Russia and some Australian states, in order to stop its potential use as an ingredient in such products. In the United States, all CB1 receptor agonists of the 3-(1-naphthylmethane)indole class such as JWH-175 are Schedule I Controlled Substances.
MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Ki of 8 nM at CB1 and 29 nM at CB2, which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).
Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.
APICA is an indole based drug that acts as a potent agonist for the cannabinoid receptors.
STS-135 (N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide, also called 5F-APICA) is a designer drug offered by online vendors as a cannabimimetic agent. The structure of STS-135 appears to use an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. STS-135 is the terminally-fluorinated analogue of SDB-001, just as AM-2201 is the terminally-fluorinated analogue of JWH-018, and XLR-11 is the terminally-fluorinated analogue of UR-144. STS-135 acts a potent cannabinoid receptor agonist in vitro, with an EC50 of 51 nM for human CB2 receptors, and 13 nM for human CB1 receptors. STS-135 produces bradycardia and hypothermia in rats at doses of 1–10 mg/kg, suggesting cannabinoid-like activity.
AB-CHMINACA is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor (Ki = 0.78 nM) and CB2 receptor (Ki = 0.45 nM) and fully substitutes for Δ9-THC in rat discrimination studies, while being 16x more potent. Continuing the trend seen in other cannabinoids of this generation, such as AB-FUBINACA and AB-PINACA, it contains a valine amino acid amide residue as part of its structure, where older cannabinoids contained a naphthyl or adamantane residue.
THJ-2201 is an indazole-based synthetic cannabinoid that presumably acts as a potent agonist of the CB1 receptor and has been sold online as a designer drug.
PX-3 (also known as APP-CHMINACA) is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor with a binding affinity of Ki = 47.6 nM and was originally developed by Pfizer in 2009 as an analgesic medication.
MMB-2201 is a potent indole-3-carboxamide based synthetic cannabinoid, which has been sold as a designer drug and as an active ingredient in synthetic cannabis blends. It was first reported in Russia and Belarus in January 2014, but has since been sold in a number of other countries. In the United States, MMB-2201 was identified in Drug Enforcement Administration drug seizures for the first time in 2018.
ADB-HEXINACA is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products, first appearing in early 2021. It is a longer chain homologue of previously encountered synthetic cannabinoid compounds such as ADB-BUTINACA and ADB-PINACA.
↑ Abbate V, et al. The ongoing challenge of novel psychoactive drugs of abuse. Part I. Synthetic cannabinoids (IUPAC Technical Report). Pure and Applied Chemistry 2018; 90(8):1256-1279. doi:10.1515/pac-2017-0605
↑ Wiley, Jenny L.; Marusich, Julie A.; Thomas, Brian F. (2016). "Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. Vol.32. pp.231–248. doi:10.1007/7854_2016_17. ISBN978-3-319-52442-9. PMID27753007.
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