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

Chemical structures of 5F-pentylindole synthetic cannabinoids showing linker and head group variations, as compared to the parent compound AM-2201.

Featured Paper of the Month – May 2022

Published in Neuropsychopharmacology by Grant Glatfelter, John Partilla and Michael Baumann of the NIDA IRP Designer Drug Research Unit.

Summary

5F-MDMB-PICA is a potent synthetic cannabinoid associated with public harm from recreational use. Little is known about the pharmacology of 5F-MDMB-PICA underlying it’s potent effects. This study examined the pharmacological effects of 5F-MDMB-PICA at cannabinoid type 1 receptors (CB1) in mice relative to several structurally related compounds. Results show that certain structural features of the “head” groups of 5F-MDMB-PICA and related compounds dramatically impacts their potencies for CB1 mediated pharmacological effects and for producing cannabinoid-like effects in mice, which is predictive of potency of these compounds in humans.

Publication Information

Glatfelter, Grant C; Partilla, John S; Baumann, Michael H

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

In: Neuropsychopharmacology, vol. 47, no. 4, pp. 924–932, 2022, ISSN: 1740-634X.

Abstract | Links

@article{pmid34802041,

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

author = {Grant C Glatfelter and John S Partilla and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/34802041/},

doi = {10.1038/s41386-021-01227-8},

issn = {1740-634X},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Neuropsychopharmacology},

volume = {47},

number = {4},

pages = {924--932},

abstract = {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 (CB), 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]rimonabant-labeled CB and displayed agonist actions in [S]GTPγS functional assays. 5F-MDMB-PICA exhibited the highest CB affinity (K = 1.24 nM) and functional potency (EC = 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 CB 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 CB involvement. In vitro K and EC values were positively correlated with in vivo ED 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 CB. Importantly, measures of CB binding and efficacy in mouse brain tissue seem to accurately predict in vivo drug potency in this species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}