Apparent Affinity Estimates and Reversal of the Effects of Synthetic Cannabinoids AM-2201, CP-47,497, JWH-122, and JWH-250 by Rimonabant in Rhesus Monkeys

J Pharmacol Exp Ther. 2017 Aug;362(2):278-286. doi: 10.1124/jpet.117.240572. Epub 2017 May 22.

Abstract

Synthetic cannabinoids have been prohibited due to abuse liability and toxicity. Four such synthetic cannabinoids, AM-2201 ([1-(5-fluoropentyl)indol-3-yl]-naphthalen-1-ylmethanone), CP-47,497 (2-[(1R,3S)-3-hydroxycyclohexyl]-5-(2-methyloctan-2-yl)phenol), JWH-122 [(4-methylnaphthalen-1-yl)-(1-pentylindol-3-yl)methanone], and JWH-250 [2-(2-methoxyphenyl)-1-(1-pentylindol-3-yl)ethanone], were tested for their capacity to produce CB1 receptor-mediated discriminative stimulus effects in two groups of rhesus monkeys. One group (n = 4) discriminated Δ9-tetrahydrocannabinol (∆9-THC; 0.1 mg/kg i.v.), and a second group (n = 4) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving 1 mg/kg/12 hours of ∆9-THC. AM-2201, JWH-122, CP-47,497, JWH-250, and ∆9-THC increased ∆9-THC lever responding. Duration of action was 1-2 hours for AM-2201, JWH-122, and JWH-250 and 4-5 hours for CP-47,497 and ∆9-THC. Rimonabant (1 mg/kg) surmountably antagonized the discriminative stimulus effects of all cannabinoid agonists; the magnitude of rightward shift was 10.6-fold for AM-2201, 10.7-fold for JWH-122, 11.0-fold for CP-47,497, and 15.7-fold for JWH-250. The respective pKB values were not significantly different: 6.61, 6.65, 6.66, and 6.83. In ∆9-THC-treated monkeys discriminating rimonabant, AM-2201 (0.1 and 0.32 mg/kg), JWH-122 (0.32 and 1 mg/kg), JWH-250 (1 and 3.2 mg/kg), and CP-47,497 (0.32, 1, and 3.2 mg/kg) produced not only rate-decreasing effects that were reversed by rimonabant, but also dose-dependent, rightward shifts in the rimonabant discrimination dose-effect function. These results show striking similarity in the CB1 receptor mechanism mediating the subjective effects of AM-2201, JWH-122, JWH-250, and CP-47,497. For products containing AM-2201 and JWH-122, a short duration of action could lead to more frequent use; moreover, inattention to differences in potency among synthetic cannabinoids could underlie unexpected toxicity. Rapid reversal of effects by intravenous rimonabant has potential value in emergency situations.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cannabinoid Receptor Antagonists / metabolism*
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cannabinoids / metabolism*
  • Cannabinoids / pharmacology
  • Cyclohexanols / metabolism*
  • Cyclohexanols / pharmacology
  • Discrimination Learning / drug effects
  • Discrimination Learning / physiology
  • Dose-Response Relationship, Drug
  • Female
  • Indoles / metabolism*
  • Indoles / pharmacology
  • Macaca mulatta
  • Male
  • Naphthalenes / metabolism*
  • Naphthalenes / pharmacology
  • Piperidines / metabolism*
  • Piperidines / pharmacology
  • Pyrazoles / metabolism*
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant

Substances

  • 1-(5-fluoropentyl)-3-(1-naphthoyl)indole
  • Cannabinoid Receptor Antagonists
  • Cannabinoids
  • Cyclohexanols
  • Indoles
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • (4-methyl-1-naphthyl)-(1-pentylindol-3-yl)methanone
  • CP 47497
  • Rimonabant