Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids

Abstract

Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.

Keywords: Alkylindoles; Aromatic stacking; Cannabinoids; Herbal marijuana; Indoles; JWH-018; Pyrroles; Review; Spice; Synthetic cannabinoids.

Figure 1

Historical 3-point attachment model used to develop JWH-018. An overlay of WIN55,212-2, Δ⁹-THC and JWH-018 was hypothesized, in which each cannabinoid would attach to the CB₁ receptor at the 3 locations specified in the figure.

Figure 2

Effects of WIN55,212-2 on spontaneous activity (panel A), antinociception (panel B), rectal temperature (panel C), and catalepsy (panel D) in adult male ICR mice. Spontaneous activity was measured as total number of photocell beam interruptions during a 10-min session and is shown as % inhibition of activity of the vehicle group. Antinociception in a tail flick assay is expressed as the percent maximum possible effect (MPE) using a 10-s maximum test latency as follows: [(test−control)/(10−control)]×100. Rectal temperature values are expressed as the difference between control temperature (before injection) and temperature following drug administration (Δ°C). During assessment for catalepsy, the total amount of time (in s) that the mouse remained motionless on the ring apparatus (except for breathing and whisker movement) was measured and was used as an indication of catalepsy-like behavior. This value was divided by 300 s and multiplied by 100 to obtain percent immobility, as shown in the figure. Values represent the mean (± SEM) of 5–6 mice per group. The typical maximal effect observed for each measure is shown in the box at the upper left of each panel. ED₅₀s for data presented in these panels are provided in Table 1.

Figure 3

Templates for major structural classes of synthetic cannabinoids discussed in this review: naphthoylindoles, naphthoylpyrroles, 1-pentyl-3-phenylacetylindoles and tetramethylcyclopropyl ketone indoles. Additional structural templates are shown in the tables.