Abstract |
Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL- PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43-12.3 nM) and CB2 (EC50 = 11.3-122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1-53 times over CB2). CUMYL- PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo.
|
Authors | Mitchell Longworth, Samuel D Banister, Rochelle Boyd, Richard C Kevin, Mark Connor, Iain S McGregor, Michael Kassiou |
Journal | ACS chemical neuroscience
(ACS Chem Neurosci)
Vol. 8
Issue 10
Pg. 2159-2167
(10 18 2017)
ISSN: 1948-7193 [Electronic] United States |
PMID | 28792725
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Cannabinoids
- Central Nervous System Agents
- Indoles
- Receptor, Cannabinoid, CB1
- Receptor, Cannabinoid, CB2
- Triazines
- indole
|
Topics |
- Animals
- Cannabinoids
(chemistry, pharmacology)
- Central Nervous System Agents
(pharmacology)
- Chromatography, Liquid
(methods)
- Humans
- Hypothermia
(chemically induced)
- Indoles
(chemistry)
- Mice
- Molecular Structure
- Rats
- Receptor, Cannabinoid, CB1
(agonists)
- Receptor, Cannabinoid, CB2
(agonists)
- Triazines
(chemistry)
|