Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor
ACS Chemical Neuroscience October 17, 2023 Hideaki Yano, Rezvan Chitsazi, Christopher Lucaj et al. 12 citations
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.