Forensic Chemistry of Substituted 1-Alkyl-3-Acylindoles: Isomeric Synthetic Cannabinoids.

The continued manufacture, distribution, importation and abuse of the synthetic cannabinoids have resulted in the recent placement of many of these compounds into Federal Schedule 1 control. These compounds have no recognized therapeutic use and pose an imminent hazard to the public safety. The synthesis of these compounds, especially the JWH compounds, is relatively straightforward and can allow for clandestine production and further designer drug development. There are a number of commercially available precursor materials to produce the substituted indoles and legal control of all these substances is not possible. Indole is readily available from many commercial suppliers and, if controlled, indole can be synthesized from other commercial precursors in essentially a one-step process. Thus, as legal controls intensify, it is likely that the clandestine production of JWH-type compounds will increase, as well as the production of new designer drug derivatives as observed over the past several decades with the amphetamine, MDMA, piperazine and bath salt classes of controlled substances. The substituted indoles represent a relatively new chemical category of drugs of abuse. Forensic chemists do not have significant experience in this area of drug/organic chemistry. It is critical that an extensive forensic chemical study for a complete series of isomeric indoles of the JWH style be made available to the forensic chemistry community. The first question to be addressed in this project concerns the uniqueness of the 1,3-indole ring substitution pattern: Are the spectral data obtained from the 1-alkyl-3-acylindoles unique to only the 1,3-indole ring substitution pattern? The precursor chemicals are available to prepare the acyl group substituted indole for every indole ring position (ie seven isomers for mono-acyl indole). While the 1-alkyl-3-acylindoles are the most likely candidates for the clandestine market, it is important for the forensic chemist to know that the analytical data generated eliminates the other isomeric indole ring substitution patterns of the equivalent substituent. Designer drug development among the indole cannabinoid compounds is another key issue of forensic importance. As regulatory controls tighten with respect to available indole cannabinoids, designer derivative exploration and synthesis is expected to grow more intense. This designer exploration will likely parallel that observed in the phenylalkylamine series of drugs and involve methoxy, dimethoxy, bromo-dimethoxy, methylenedioxy, trifluoromethyl, chloro, and methyl substituents, as well as regiosiomers of these substitution patterns. These aromatic ring substituents are known to enhance CNS hallucinogenic or entactogenic activity in the phenethylamines, bath salt and piperazine drugs of abuse. Many of these aromatic ring substituted precursor materials are commercially available and can be readily incorporated into the structural framework of the JWH-style indole cannabinoid compounds. It could be argued that isomer differentiation is not necessary in forensic science based on the U. S. Controlled Substance Analog Act. The law should make all these isomers controlled substances. However the forensic chemist is faced with the same basic dilemma: The compound must be specifically identified in order to know if it is an analog of a controlled substance. A proactive investigation of the forensic analytical chemistry of these future designer substances is an objective of this project. The resulting analytical data and methods represent important advancements in forensic drug chemistry. The relationship between drug/isomer structure and analytical properties such as mass spectral fragmentation will be evaluated by the synthesis of labeled (isotopic and homologous labels) synthetic cannabinoid compounds. ca/ncf