JWH-018 and M1–M5 activate CB1R.

<p><b>A.</b> Ten µM concentrations of JWH-018, M1, M2, M3, and M5 activated brain GPCRs greater than 10 µM Δ⁹-THC. Activation by JWH-018, M2, M3 and M5 did not differ from the full CB1R agonist CP-55,940. Values designated with different letters above the error bars are significantly different (P<0.05, one way ANOVA with Tukey's Multiple Comparison <i>post-hoc</i> Test, n = 3–10). <b>B.</b> JWH-018 and M1 stimulated G-proteins more potently and efficaciously than Δ⁹-THC, n = 3–4. <b>C.</b> GPCR activation by an estimated ED₉₀ concentration (100 nM) of metabolites was blocked by co-incubation with 1 µM of the selective neutral CB1R antagonist O-2050 (**<i>P</i><0.01, ***<i>P</i><0.001 vs drug alone, Student's <i>t</i>-test, n = 3–7).</p

JWH-018 and M1 decreased mouse locomotor activity in a CB1R-dependent manner, similar to Δ⁹-THC.

<p><b>A.</b> Intraperitoneal (i.p.) administration of 3 mg/kg JWH-018, 10 mg/kg JWH-018 M1, and 30 mg/kg Δ⁹-THC decreased locomotor activity relative to vehicle controls over a 10 h time course, beginning 60 min after injection. <b>B.</b> Area under the curve data generated from the 10 h time-course shows 3 mg/kg JWH-018, 10 mg/kg JWH-018 M1, and 30 mg/kg Δ⁹-THC significantly decrease locomotor activity relative to vehicle controls (*<i>P</i><0.05 vs. vehicle controls, Kruskal-Wallis one-way ANOVA with Tukey HSD test, n = 5). Co-administration of each cannabinoid with the CB1R-preferring antagonist/inverse agonist AM251 (10 mg/kg) restored locomotor activity to vehicle control levels.</p

Structures of JWH-018 and six JWH-018 hydroxylated products.

<p><b>A. JWH-018</b> [(1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone] <b>B. M1</b> [(4-hydroxy-1-pentyl-1H-indol-3-yl)(naphthalen-1-yl)methanone] <b>C. M2</b> [(5-hydroxy-1-pentyl-1H-indol-3-yl)(naphthalen-1-yl)methanone] <b>D. M3</b> [(6-hydroxy-1-pentyl-1H-indol-3-yl)(naphthalen-1-yl)methanone] <b>E. M4</b> [(7-hydroxy-1-pentyl-1H-indol-3-yl)naphthalen-1-yl)methanone] <b>F. M5</b> [(1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone] <b>G. M6</b> [5-(3-(1-naphthoyl)-1H-indol-1-yl)pentanoic acid].</p

JWH-018 and M1 decreased mouse core body temperature in a CB1R-dependent manner similar to Δ⁹-THC.

<p><b>A.</b> Mice administered 3 mg/kg JWH-018 and 10 mg/kg M1 (i.p.) exhibited greater depressions in core body temperature than 30 mg/kg Δ⁹-THC, but also recovered more quickly over a 10 h time course, resulting in <b>B.</b> equivalent area under the curve values, which were significantly lower than vehicle controls (*<i>P</i><0.005 vs. vehicle controls, one-way ANOVA with Tukey HSD test, n = 5). Core body temperature was restored to vehicle control levels by coadministration of cannabinoids with the CB1R-preferring antagonist/inverse agonist AM251 (10 mg/kg).</p