Structure-activity relationships for 5F-MDMB-PICA and its 5F-pentylindole analogs to induce cannabinoid-like effects in mice

Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances found on recreational drug markets worldwide. The indole-containing compound, 5F-MDMB-PICA, is a popular SCRA associated with serious medical consequences, including overdose and hospitalizations. In vitro studies reveal that 5F-MDMB-PICA is a potent agonist at cannabinoid type 1 receptors (CB1), but little information exists regarding in vivo pharmacology of the drug. To this end, we examined the in vitro and in vivo cannabinoid-like effects produced by 5F-MDMB-PICA and related 5F-pentylindole analogs with differing composition of the head group moiety (i.e., 5F-NNEI, 5F-SDB-006, 5F-CUMYL-PICA, 5F-MMB-PICA). In mouse brain membranes, 5F-MDMB-PICA and its analogs inhibited binding to [H-3]rimonabant-labeled CB1 and displayed agonist actions in [S-35]GTP gamma S functional assays. 5F-MDMB-PICA exhibited the highest CB1 affinity (K-i = 1.24 nM) and functional potency (EC50 = 1.46 nM), but head group composition markedly influenced activity in both assays. For example, the 3,3-dimethylbutanoate (5F-MDMB-PICA) and cumyl (5F-CUMYL-PICA) head groups engendered high CB1 affinity and potency, whereas a benzyl (5F-SDB-006) head group did not. In C57BL/6J mice, all 5F-pentylindole SCRAs produced dose- and time-dependent hypothermia, catalepsy, and analgesia that were reversed by rimonabant, indicating CB1 involvement. In vitro K-i and EC50 values were positively correlated with in vivo ED50 potency estimates. Our findings demonstrate that 5F-MDMB-PICA is a potent SCRA, and subtle alterations to head group composition can have profound influence on pharmacological effects at CB1. Importantly, measures of CB1 binding and efficacy in mouse brain tissue seem to accurately predict in vivo drug potency in this species.

Automated summary

Synthetic cannabinoid receptor agonists (SCRAs) are a new class of psychoactive substances found on recreational drug markets worldwide. 5F-MDMB-PICA, a popular SCRA, is a potent agonist at CB1 receptors. In vitro and in vivo studies showed that subtle alterations to head group composition can have profound influence on pharmacological effects at CB1. The SCRA-induced effects in mice such as hypothermia, catalepsy, and analgesia were dose- and time-dependent and reversed by rimonabant, indicating CB1 involvement.