Synthetic cannabinoids (SCs) like AM2201 and JWH-018, but not the phytocannabinoid Δ9-tetrahydrocannabinol, act as positive allosteric modulators (PAMs) at the 5-HT1A receptor, a noncannabinoid site. In vitro, AM2201 potentiated 5-HT1A agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons. In mice lacking cannabinoid receptor 1, AM2201 also potentiated the hypothermic response to 5-HT1A receptor stimulation. These findings suggest that PAM activity at 5-HT1A receptors may be a novel noncannabinoid mechanism contributing to the adverse effects of certain synthetic cannabinoids.
Minor chemical changes in synthetic cannabinoid receptor agonists (SCRAs) can dramatically increase their potency and efficacy at the CB1 receptor, making them far more toxic than THC. Using bioluminescence assays and hippocampal slice recordings, the authors found that adding a single methyl group to the head moiety of 5F-MMB-PICA (producing 5F-MDMB-PICA) greatly enhanced G protein signaling and β-arrestin recruitment. Molecular modeling showed how this small structural difference propagated to the receptor-G protein interface, explaining the heightened activity. These findings underscore the need for close surveillance of structural modifications in newly emerging SCRAs due to their potential for severe toxicity in humans.