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Putative Synthetic Cannabinoids MEPIRAPIM, 5F-BEPIRAPIM (NNL-2), and Their Analogues Are T-Type Calcium Channel (CaV3) Inhibitors.
Kevin, Richard C; Mirlohi, Somayeh; Manning, Jamie J; Boyd, Rochelle; Cairns, Elizabeth A; Ametovski, Adam; Lai, Felcia; Luo, Jia Lin; Jorgensen, William; Ellison, Ross; Gerona, Roy R; Hibbs, David E; McGregor, Iain S; Glass, Michelle; Connor, Mark; Bladen, Chris; Zamponi, Gerald W; Banister, Samuel D.
Affiliation
  • Kevin RC; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
  • Mirlohi S; School of Pharmacy, The University of Sydney, NSW 2006, Australia.
  • Manning JJ; Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW 2109, Australia.
  • Boyd R; Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New Zealand.
  • Cairns EA; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
  • Ametovski A; School of Chemistry, The University of Sydney, NSW 2006, Australia.
  • Lai F; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
  • Luo JL; School of Psychology, The University of Sydney, NSW 2006, Australia.
  • Jorgensen W; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
  • Ellison R; School of Chemistry, The University of Sydney, NSW 2006, Australia.
  • Gerona RR; School of Pharmacy, The University of Sydney, NSW 2006, Australia.
  • Hibbs DE; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
  • McGregor IS; School of Psychology, The University of Sydney, NSW 2006, Australia.
  • Glass M; School of Chemistry, The University of Sydney, NSW 2006, Australia.
  • Connor M; Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, California 94143, United States.
  • Bladen C; Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, California 94143, United States.
  • Zamponi GW; School of Pharmacy, The University of Sydney, NSW 2006, Australia.
  • Banister SD; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
ACS Chem Neurosci ; 13(9): 1395-1409, 2022 05 04.
Article in En | MEDLINE | ID: mdl-35442021
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cannabinoids / Calcium Channels, T-Type / Hypothermia Limits: Animals Language: En Journal: ACS Chem Neurosci Year: 2022 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cannabinoids / Calcium Channels, T-Type / Hypothermia Limits: Animals Language: En Journal: ACS Chem Neurosci Year: 2022 Document type: Article