Cannabinoids in disguise: Δ9-Tetrahydrocannabinol-like effects of tetramethylcyclopropyl ketone indoles

Abstract

Synthetic indole-derived cannabinoids have become commonly used recreational drugs and continue to be abused despite their adverse consequences. As compounds that were identified early in the epidemic (e.g., naphthoylindoles) have become legally banned, new compounds have appeared on the drug market. Two tetramethylcyclopropyl ketone indoles, UR-144 [(1-pentyl-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone] and XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone], recently have been identified in confiscated products. These compounds are structurally related to a series of CB2-selective compounds explored by Abbott Labs. The purpose of the present study was to evaluate the extent to which UR-144 and XLR-11 shared cannabinoid effects with Δ9-tetrahydrocannabinol (Δ9-THC). Indices of in vitro and in vivo activity at cannabinoid receptors were assessed. Similar to other psychoactive cannabinoid agonists, XLR-11 and UR-144 showed low nanomolar (< 30) affinity for CB1 and CB2 receptors, activated these receptors as full agonists, and produced dose-dependent effects that were blocked by rimonabant in mice, including antinociception, hypothermia, catalepsy and suppression of locomotor activity. The potency of both compounds was several-fold greater than Δ9-THC. XLR-11 and UR-144 also substituted for Δ9-THC in a Δ9-THC discrimination procedure in mice, effects that were attenuated by rimonabant. Analysis of urine from mice treated with the compounds revealed that both were extensively metabolized, with predominant urinary excretion as glucuronide conjugates. Together, these results demonstrate that UR-144 and XLR-11 share a pharmacological profile of in vitro and in vivo effects with Δ9-THC and other abused indole-derived cannabinoids and would be predicted to produce Δ9-THC-like subjective effects in humans.

AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol–Like Effects in Mice

“…Previously, we have observed response rate decreases only with doses of other synthetic cannabinoids that were suprathreshold for full substitution ( Fig. 5; Wiley et al, 1995aWiley et al, , 2013. Hence, AB-PINACA's lack of separation between doses that were D 9 -THC-like and those that substantially suppressed responding was unusual compared with the profile seen with other synthetic cannabinoids.…”

“…All in vitro and in vivo experimental procedures were similar to those described in our previous publication (Wiley et al, 2013), in which we described results of tests with two tetramethylcyclopropyl ketone indoles, XLR-11 and UR-144, that are also classified as synthetic cannabinoids of abuse.…”

“…A dose-effect curve was determined with D 9 -THC in both groups of mice. The first group of mice was subsequently tested with several cannabinoid tricyclic dibenzopyran analogs (data not shown) and with two indole-derived synthetic cannabinoids (Wiley et al, 2013). In the present study, the first group of mice was tested with JWH-018, WIN55,212-2, and CP47,497, and a second dose-effect curve was determined D 9 -THC.…”

Next generation of novel psychoactive substances on the horizon – A complex problem to face

“…UR-144 ('KM X-1') has been designed by Abbott Laboratories in a search for selective agonists of cannabinoid CB 2 receptors (Frost et.al., 2010). The compound preferentially binds to peripheral CB 2 receptors over brain CB 1 receptors (Wiley et al, 2013). 5F-UR-144 (XLR-11), a 5-fluorinated analogue of UR-144, is a potent full agonist of CB 1 and CB 2 receptors.…”

Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB₁ receptor and cannabimimetic effects in mice

“…Although UR-144 induces hypothermia and reduces locomotor activity in experimental animals (Wiley et al, 2013;Gatch and Forster, 2015;Banister et al, 2015), the effects are weaker than other typical synthetic cannabinoids such as JWH-018 and AM-2201 (Banister et al, 2015). It is possible that these phenomena are explained by receptor selectivity of UR-144, as its Ki values are 150 nM and 1.8 nM for CB 1 and CB 2 , respectively (Frost et al, 2010).…”