Putative synthetic cannabinoids MEPIRAPIM, 5F-BEPIRAPIM (NNL-2), and their analogues are T-type calcium channel (CaV3) inhibitors

Richard C. Kevin, Somayeh Mirlohi, Jamie Manning, Rochelle Boyd, Elizabeth A. Cairns, Adam Ametovski, Felcia Lai, Jia Lin Luo, William Jorgensen, Ross Ellison, Roy R. Gerona, David E. Hibbs, Iain S. McGregor, Michelle Glass, Mark Connor, Chris Bladen, Gerald W. Zamponi, Samuel D. Banister

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4 Citations (Scopus)


Synthetic cannabinoid receptor agonists (SCRAs) are a large and growing class of new psychoactive substances (NPSs). Two recently identified compounds, MEPIRAPIM and 5F-BEPIRAPIM (NNL-2), have not been confirmed as agonists of either cannabinoid receptor subtype but share structural similarities with both SCRAs and a class of T-type calcium channel (CaV3) inhibitors under development as new treatments for epilepsy and pain. In this study, MEPIRAPIM and 5F-BEPIRAPIM and 10 systematic analogues were synthesized, analytically characterized, and pharmacologically evaluated using in vitro cannabinoid receptor and CaV3 assays. Several compounds showed micromolar affinities for CB1 and/or CB2, with several functioning as low potency agonists of CB1 and CB2 in a membrane potential assay. 5F-BEPIRAPIM and four other derivatives were identified as potential CaV3 inhibitors through a functional calcium flux assay (>70% inhibition), which was further confirmed using whole-cell patch-clamp electrophysiology. Additionally, MEPIRAPIM and 5F-BEPIRAPIM were evaluated in vivo using a cannabimimetic mouse model. Despite detections of MEPIRAPIM and 5F-BEPIRAPIM in the NPS market, only the highest MEPIRAPIM dose (30 mg/kg) elicited a mild hypothermic response in mice, with no hypothermia observed for 5F-BEPIRAPIM, suggesting minimal central CB1 receptor activity.
Original languageEnglish
Pages (from-to)1395-1409
Number of pages15
JournalACS Chemical Neuroscience
Issue number9
Early online date20 Apr 2022
Publication statusPublished - 4 May 2022


  • cannabinoid
  • NNL
  • pharmacology
  • calcium channel


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