title: AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol-Like Effects in Mice.
abstract: Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-CHMINACA (N-[1-amino-3-methyl-oxobutan-2-yl]-1-[cyclohexylmethyl]-1H-indazole-3-carboxamide), AB-PINACA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide], and FUBIMINA [(1-(5-fluoropentyl)-1H-benzo[d]imadazol-2-yl)(naphthalen-1-yl)methanone], with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB1 receptors, and in vivo for pharmacological effects in mice and in Δ(9)-tetrahydrocannabinol (Δ(9)-THC) discrimination. AB-CHMINACA, AB-PINACA, and FUBIMINA bound to and activated CB1 and CB2 receptors, and produced locomotor suppression, antinociception, hypothermia, and catalepsy. Furthermore, these compounds, along with JWH-018 [1-pentyl-3-(1-naphthoyl)indole], CP47,497 [rel-5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol], and WIN55,212-2 ([(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone, monomethanesulfonate), substituted for Δ(9)-THC in Δ(9)-THC discrimination. Rank order of potency correlated with CB1 receptor-binding affinity, and all three compounds were full agonists in [(35)S]GTPγS binding, as compared with the partial agonist Δ(9)-THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids.
authors.affiliation: RTI International, Research Triangle Park, North Carolina jwiley@rti.org bft@rti.org.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Marusich
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lefever
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Kateland R
authors.initials: KR
authors.lastname: Antonazzo
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wallgren
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Cortes
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Purvi R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Megan
authors.initials: M
authors.lastname: Grabenauer
authors.affiliation: RTI International, Research Triangle Park, North Carolina.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Moore
authors.affiliation: RTI International, Research Triangle Park, North Carolina jwiley@rti.org bft@rti.org.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism; D006900:Hydroxylation / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced; D013287:Illicit Drugs / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism
chemical_list: D000700:Analgesics; D002186:Cannabinoids; D063388:Endocannabinoids; D013287:Illicit Drugs; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol