1-Pentyl-3-phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice - PubMed (original) (raw)

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

Jenny L Wiley et al. Drug Alcohol Depend. 2012.

Abstract

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.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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Conflict of interest statement

5.3 Conflicts of interst

All of the authors declare that they have no conflicts of interest.

Figures

Figure 1

Figure 1

Chemical structures of THC and JWH-018. The structural template for the 1-pentyl-3-phenylacetylindoles is also shown, with positions of R and R′ groups indicated (see Tables 1 and 2).

Figure 2

Figure 2

Scatterplots and regression lines for CB1 affininities (log Ki) plotted against log ED50 for each of the three in vivo tests (SA = spontaneous activity, top left panel; MPE = % maximum possible antinociceptive effect, top right panel; RT = change in rectal temperature, bottom left panel). The bottom right panel shows scatterplot and regression line for the relationship between CB1 and CB2 binding affinities (log Kis). Pearson product-moment correlations are shown for the two measures graphed in each panel. * indicates significant correlation (p<0.05).

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