1-Pentyl-3-phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice

Drug Alcohol Depend. 2012 Jun 1;123(1-3):148-53. doi: 10.1016/j.drugalcdep.2011.11.001. Epub 2011 Nov 27.


Background: Smoking of synthetic cannabinoid-enhanced "herbal incense" is an emerging substance abuse problem. The indole-derived cannabinoids identified in these products were originally developed as research tools and are structurally distinct from cannabinoids in the cannabis plant. Although abused by humans, most published research on this class of compounds has been performed in vitro. The purpose of this study was to evaluate a novel series of 1-pentyl-3-phenylacetylindoles in mice.

Methods: The potencies of these analogs to produce the cannabinoid agonist effects of antinociception, hypothermia and suppression of locomotion were evaluated in ICR mice. The major structural manipulations in the present series included the type of substituent (i.e., unsubstituted, methyl, methoxy, chloro, bromo, and fluoro) and the position of the substituent on the phenyl ring (i.e., 2-, 3- or 4-position).

Results: Potencies of this series of phenylacetylindoles for each cannabinoid effect were highly correlated with CB(1) receptor affinities reported previously. Active compounds produced a profile of effects that resembled that exhibited by Δ(9)-tetrahydrocannabinol (THC). The most critical factor affecting in vivo potency was the position of the substituent. Whereas compounds with 2- and 3-phenylacetyl substituents were efficacious with good potencies, 4-substituents resulted in compounds that had poor potency or were inactive.

Conclusions: These results suggest that phenylacetylindoles with good CB(1) binding affinity share pharmacological properties with THC in mice; however, they also emphasize the complexity of molecular interactions of synthetic cannabinoids with CB(1) receptors and suggest that scheduling efforts based solely upon structural features should proceed with caution.

Publication types

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

MeSH terms

  • Analgesics
  • Animals
  • Cannabinoids / agonists*
  • Cannabinoids / chemical synthesis*
  • Cannabinoids / metabolism
  • Dronabinol / pharmacology
  • Hypothermia / chemically induced
  • Indoles / chemical synthesis
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Naphthalenes / pharmacology*
  • Pain Measurement / drug effects
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism
  • Structure-Activity Relationship


  • Analgesics
  • Cannabinoids
  • Indoles
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Dronabinol
  • 1-pentyl-3-(1-naphthoyl)indole