Cannabinoids in disguise: Δ9-tetrahydrocannabinol-like effects of tetramethylcyclopropyl ketone indoles.
Jenny L Wiley, Julie A. Marusich, Timothy W Lefever, Megan Grabenauer, Katherine N Moore, Brian F Thomas
Neuropharmacology December 2013 DOI: 10.1016/j.neuropharm.2013.07.022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical in vitro and in vivo pharmacology study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | UR-144 XLR-11 Δ9-tetrahydrocannabinol (Δ9-THC) rimonabant |
| Topics | Cannabis |
| Keywords | Abuse liability Delta-9-tetrahydrocannabinol Drug discrimination Synthetic cannabinoids Ur-144 Xlr-11 |
| Key points | UR-144 and XLR-11 bound CB1 and CB2 receptors with low nanomolar affinity (under 30), acted as full agonists, and in mice produced dose-dependent antinociception, hypothermia, catalepsy, and locomotor suppression blocked by rimonabant. Both were several-fold more potent than Δ9-THC and substituted for Δ9-THC in a discrimination procedure, leading the authors to conclude they share Δ9-THC's pharmacological profile and would be predicted to produce Δ9-THC-like subjective effects in humans. |
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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 21
- Baths Salts, Spice, and Related Designer Drugs: The Science Behind the Headlines Journal of Neuroscience November 12, 2014
- Sex and Gender Differences in the Effects of Novel Psychoactive Substances. Brain Sciences September 3, 2020
- Disruption of hippocampal synaptic transmission and long‐term potentiation by psychoactive synthetic cannabinoid ‘Spice’ compounds: comparison with Δ9‐tetrahydrocannabinol Addiction Biology January 5, 2016
- Optogenetic brain‐stimulation reward: A new procedure to re‐evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter‐Cre mice Addiction Biology February 3, 2021
- Acute Pharmacological Effects and Oral Fluid Biomarkers of the Synthetic Cannabinoid UR-144 and THC in Recreational Users Biology March 24, 2021
and 16 more in the library
Cites 9
- Inhalation exposure to smoke from synthetic "marijuana" produces potent cannabimimetic effects in mice. Drug and Alcohol Dependence December 1, 2012
- 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism. Journal of Pharmacology and Experimental Therapeutics February 2012
- JWH-018 and JWH-073: Δ⁹-tetrahydrocannabinol-like discriminative stimulus effects in monkeys. Journal of Pharmacology and Experimental Therapeutics January 2012
- Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (Δ(9)-tetrahydrocannabinol) discrimination for rats. Behavioural Pharmacology September 2011
- JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. British Journal of Pharmacology June 2010
and 4 more in the library