Title: New psychoactive substances: from criminal to clinical
Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest classes of new psychoactive substances (NPS). More than 300 examples have been identified in drug markets worldwide since the first examples were detected around 2008. Clandestine manufacturers design new SCRAs using medicinal chemistry techniques such as molecular hybridization, bioisosteric replacement and scaffold hopping, and many SCRAs are unknown in the scientific literature before their detection in drug markets. Concerningly, SCRAs are increasingly associated with mass intoxications involving severe illness and often death.
We have used a systematic, combinatorial synthetic approach to rapidly and proactively develop a library of hundreds of recent and anticipated "prophetic" SCRAs and metabolites based on design trends in the SCRA marketplace. The SCRA library was screened at human CB1 and CB2 receptors using a suite of binding and functional assays and evaluated in mice using radiobiotelemetry. Many SCRAs demonstrated potent cannabimimetic activity in vitro and in vivo, with distinct profiles to Δ9-THC from cannabis. Several SCRAs showed potent proconvulsant activity in mice, consistent with clinical reports of seizure following ingestion.
Through the Psychoactive Surveillance Consortium and Analysis Network (PSCAN), we used LC-QTOF-MS to screen for all members of the library in patient samples from several partner sites across the US, identifying several novel SCRAs for the first time. The proactive generation of NPS analogue libraries represents an innovative strategy for the detection of emerging drugs of abuse by forensic and clinical toxicologists.