title: Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA.
abstract: Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Michael
authors.initials: M
authors.lastname: Moir
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Jordyn
authors.initials: J
authors.lastname: Stuart
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kevin
authors.forename: Katie E
authors.initials: KE
authors.lastname: Wood
authors.forename: Mitchell
authors.initials: M
authors.lastname: Longworth
authors.forename: Shane M
authors.initials: SM
authors.lastname: Wilkinson
authors.forename: Corinne
authors.initials: C
authors.lastname: Beinat
authors.affiliation: Department of Anaesthesia, Prince of Wales Hospital , Randwick, NSW 2031, Australia.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Buchanan
authors.affiliation: School of Medical Sciences, The University of Auckland , Auckland 1142, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015198:Designer Drugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C571130:CNR1 protein, human; C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D015198:Designer Drugs; D007191:Indazoles; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: Cannabinoid; FUBINACA; JWH-018; PINACA; THC