A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors.
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ABSTRACT:
SUBMITTER: Seely KA
PROVIDER: S-EPMC3921679 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
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A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors.
Seely Kathryn A KA Brents Lisa K LK Radominska-Pandya Anna A Endres Gregory W GW Keyes Gregory S GS Moran Jeffery H JH Prather Paul L PL
Chemical research in toxicology 20120315 4
Recently, hydroxylated metabolites of JWH-018, a synthetic cannabinoid found in many K2/Spice preparations, have been shown to retain affinity and activity for cannabinoid type 1 receptors (CB1Rs). The activity of glucuronidated metabolites of JWH-018 is not known; hence, this study investigated the affinity and activity of a major metabolite, JWH-018-N-(5-hydroxypentyl) β-D-glucuronide (018-gluc), for CB1Rs. The 018-gluc binds CB1Rs (K(i) = 922 nM), has no effect on G-protein activity, but anta ...[more]
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Project description:Synthetic cannabinoids (SCs) are a significant public health concern given their widespread use and severe effects associated with intoxication. However, there is a paucity of controlled human studies investigating the behavioral and physiological effects and pharmacokinetics of these compounds. Designing a reliable method to administer consistent, concentration-dependent synthetic cannabinoids is an integral component of controlled study of these compounds. Further, optimizing methods to assess the parent compounds and metabolites in plasma is critical in order to be able to establish their pharmacokinetics after administration. To develop a reliable method to administer smokable, concentration-dependent SCs, cigarettes were prepared with plant matter adulterated with increasing concentrations of the first generation cannabinoids found in SC products, JWH-018 and JWH-073. Cigarettes were assessed 1-6 months after preparation using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to determine compound stability over time and concentration consistency throughout the cigarettes. Optimal conditions to detect metabolites in human plasma as a function of storage temperature (-4 °C to -80 °C) and time (24 h - 1 month) were also determined. Analyses verified that the method utilized to develop SC cigarettes yielded consistent, concentration-dependent products within 25% of the expected concentrations. JWH-018, JWH-073 and metabolites in spiked plasma were stable under the time and temperature conditions; concentrations were within ±20% of target values. These studies provide techniques and methods to conduct controlled investigations of the dose-dependent effects of first generation SCs to begin understanding risks associated with use. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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| S-EPMC3105467 | biostudies-other
Project description:Synthetic cannabinoids JWH-018, JWH-073 and AM2201 were metabolised by the fungus Cunninghamella elegans. In this article, data on individual metabolites of their retention times, mass accuracies, major product ions and structures indicated by product ions are presented. The data in this article is related to "Biotransformation of synthetic cannabinoids JWH-018, JWH-073 and AM2201 by Cunninghamella elegans" [1].
| S-EPMC4781962 | biostudies-literature
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Project description:BackgroundDisturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses.MethodsWe used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional magnetic resonance imaging. Volunteers rated pleasantness, intensity, and wanting for each stimulus.ResultsThere were no significant differences between groups in subjective ratings. However, tetrahydrocannabivarin increased responses to chocolate stimuli in the midbrain, anterior cingulate cortex, caudate, and putamen. Tetrahydrocannabivarin also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen.ConclusionsOur findings are the first to show that treatment with the CB1 neutral antagonist tetrahydrocannabivarin increases neural responding to rewarding and aversive stimuli. This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects.
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Project description:Synthetic cannabinoids can cause acute adverse psychological effects, but the potential impact when exposure happens before birth is unknown. Use of synthetic cannabinoids during pregnancy may affect fetal brain development, and such effects could be moderated by the genetic makeup of an individual. Disrupted in schizophrenia 1 (DISC1) is a gene with important roles in neurodevelopment that has been associated with psychiatric disorders in pedigree analyses. Using zebrafish as a model, we investigated (1) the behavioral impact of developmental exposure to 3 μM 1-pentyl-3-(1-naphthoyl)-indole (JWH-018; a common psychoactive synthetic cannabinoid) and (2) whether disc1 moderates the effects of JWH-018. As altered anxiety responses are seen in several psychiatric disorders, we focused on zebrafish anxiety-like behavior. Zebrafish embryos were exposed to JWH-018 from one to six days post-fertilization. Anxiety-like behavior was assessed using forced light/dark and acoustic startle assays in larvae and novel tank diving in adults. Compared to controls, both acutely and developmentally exposed zebrafish larvae had impaired locomotion during the forced light/dark test, but anxiety levels and response to startle stimuli were unaltered. Adult zebrafish developmentally exposed to JWH-018 spent less time on the bottom of the tank, suggesting decreased anxiety. Loss-of-function in disc1 increased anxiety-like behavior in the tank diving assay but did not alter sensitivity to JWH-018. Results suggest developmental exposure to JWH-018 has a long-term behavioral impact in zebrafish, which is not moderated by disc1.
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