Structural scheduling of synthetic cannabinoids

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.

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.