title: Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues.
abstract: Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45-36 nM) and CB2 (EC50 = 4.6-128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1-1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB1, but not CB2, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ(9)-THC and earlier generations of SCs.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine , Stanford, California 94305, United States.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Mitchell
authors.initials: M
authors.lastname: Longworth
authors.forename: Richard
authors.initials: R
authors.lastname: Kevin
authors.affiliation: Department of Biomedical Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Shivani
authors.initials: S
authors.lastname: Sachdev
authors.affiliation: Department of Biomedical Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Santiago
authors.affiliation: Department of Biomedical Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Jordyn
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94304, United States.
authors.forename: James B C
authors.initials: JB
authors.lastname: Mack
authors.affiliation: School of Medical Sciences, The University of Auckland , Auckland 1142, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
authors.affiliation: Department of Biomedical Sciences, Macquarie University , Sydney, NSW 2109, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology*; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D007191:Indazoles; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C000614253:methyl (1-(5-fluoropentyl)-1H-indazole-3-carbonyl)valinate; C000613980:methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate; C000610109:methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate; C089871:2-amino-3,3-dimethylbutanoic acid; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C030374:indole; D007930:Leucine; D014633:Valine; C000616976:5F-ADB cannabinoid
keywords: AMB; Cannabinoid; JWH-018; MDMB; THC