Are new compounds spicing up the synthetic cannabinoid receptor agonist market?

Abstract

Objective

Investigation of the evolution and pharmacological characteristics of newly emerging synthetic cannabinoid receptor agonists.

Introduction

The synthetic cannabinoid receptor agonist (SCRA) market is constantly evolving and diversifying. Since the emergence of JWH-018 as the first ‘legal high’, designed to circumvent the ban on cannabis, a whole array of compounds have been introduced to the public (followed by equally as many legislative actions) in a true cat-and-mouse game fashion. The enactment of the Chinese generic SCRA ban in 2021 has caused important changes in the recreational drug landscape. Since then, a large set of ‘ban-evading’ substances with a vast structural diversity and never-seen-before features have continuously entered the market. As a consequence, a staggering amount of new, uncharacterized, substances has become available for users who are unaware of the potential health hazards that may be associated with the use of these products. This presentation will elaborate on the recent dynamics in the SCRA market, focusing on the diversity of compounds and the challenges this poses for forensic institutes. An important emphasis will lie on the pharmacological characterization and potential harms of these new substances.

Methods

Pharmacological properties of an extensive set of newly emerging SCRAs were investigated. To accomplish this, their CB₁ cannabinoid receptor activation potential was evaluated using in vitro live cell β-arrestin 2 recruitment assays, based on functional complementation of a split nanoluciferase enzyme and the measurement of bioluminescence.

Results

Moving on from the typical JWH-018-like head-core-tail structure, the SCRA market now encompasses a plethora of diverse chemical structures, which are the result of several strategies to evade the Chinese generic SCRA ban. A first strategy included compounds with alternative cores not covered by the legislation. Examples are oxoindolin and oxopyridone cores, yielding OXIZID SCRAs and CH-FUBBMPDORA, respectively, which have a (strongly) reduced potency. An alternative strategy is the insertion of an additional methylene linker (such as for ADB-FUBIATA and CH-PIATA), which also resulted in poor CB₁ activity. On the other hand, adding a halogen atom to a typical indazole core yielded substances with a high potency and efficacy, as exemplified by the brominated ADB-5′Br-BUTINACA. This is relevant, as the high potency of this compound may also pose analytical challenges, as relevant concentrations may be very low. Moving the tail moiety to another position in the molecule yielded compounds with almost no activity (e.g., 5F-3,5-AB-PFUPPYCA). Also, removing the tail (as seen in ADB-INACA, MDMB-INACA) resulted in a reduced activity. However, a new phenomenon referred to as “Do-It-Yourself” (DIY) SCRAs appears to be one of the latest ploys to bypass the legislation. So-called “semi-finished SCRAs” are now being advertised online and are often tail-less (ban-evading) compounds (such as MDMB-INACA). These are sometimes even shipped together with the instructions and materials needed to obtain a scheduled SCRA via rather straightforward chemical synthesis at home. This new strategy is potentially very dangerous, as it allows users to obtain (via a detour) potentially very potent compounds (such as MDMB-PINACA synthesized from MDMB-INACA), without the threat of committing a criminal offence for purchasing said compound.

Conclusion

Given the dynamic SCRA market and the concomitant challenges, the continuous pharmacological characterization of newly emerging SCRAs provides valuable and essential information to inform both drug law enforcement agencies and healthcare workers. This information is relevant from a harm reduction perspective, and for prioritization purposes (i.e., to define those compounds that may potentially bear the highest risk). It can be expected that this ever-lasting cat-and-mouse game that describes the SCRA landscape will carry on, with the surge of new and unexpected substances remaining a significant challenge – whether legislative, pharmacologically or analytically.