TY - JOUR
T1 - Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues
AU - Longworth, Mitchell
AU - Banister, Samuel D.
AU - Boyd, Rochelle
AU - Kevin, Richard C.
AU - Connor, Mark
AU - McGregor, Iain S.
AU - Kassiou, Michael
PY - 2017/10/18
Y1 - 2017/10/18
N2 - 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.
AB - 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.
KW - Cannabinoid
KW - CUMYL-5F-PICA
KW - CUMYL-5F-PINACA
KW - CUMYL-BICA
KW - CUMYL-PICA
KW - CUMYL-PINACA
UR - http://www.scopus.com/inward/record.url?scp=85031691223&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/1107088
U2 - 10.1021/acschemneuro.7b00267
DO - 10.1021/acschemneuro.7b00267
M3 - Article
C2 - 28792725
AN - SCOPUS:85031691223
SN - 1948-7193
VL - 8
SP - 2159
EP - 2167
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 10
ER -