Novel halogenated derivates of JWH-018: Behavioral and binding studies in mice

Vigolo, A.; Ossato, Andrea; Trapella, Claudio; Vincenzi, Fabrizio; Rimondo, Claudia; Seri, Catia; Varani, Katia; Serpelloni, Giovanni; Marti, Matteo

doi:10.1016/j.neuropharm.2015.02.008

Cited by 83 publications

(177 citation statements)

References 51 publications

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“…As recently reported (Vigolo et al, 2015), JWH-018 administrated at the highest dose (6 mg/kg i.p.) induced spontaneous and handling-induced convulsions, hyperreflexia and myoclonias in mice which persisted up to 15 min after drug administration.…”

Section: Major Neurological Changessupporting

confidence: 60%

“…In particular, we demonstrated that alterations of sensorimotor responses were caused by the administration of low doses of JWH-018 and D 9 -THC (0.01 and 0.1 mg/kg) which did not impair spontaneous motor performance in mice. With increasing dose, JWH-018 induced a marked motor impairment and at the highest dose tested it caused seizures, myoclonus and hyperreflexia (Marshell et al, 2014;Vigolo et al, 2015). In contrast, D 9 -THC inhibited sensorimotor responses in mice without reducing motor activity and without causing neurological disorders.…”

Section: Discussionmentioning

confidence: 92%

“…In the present study JWH-018 doses were chosen based on previous studies in mice (Macri et al, 2013a,b;Vigolo et al, 2015) and on behavioral and neurological effects reported in human volunteers. In fact, based on personal experiences of consumers of JWH-018 (http://www.erowid.org/experiences/subs/exp_ JWH018.shtml), it can be assumed that increasing doses up to $0.15 mg/kg produce progressive onset of pleasurable and dysperceptive effects similar to cannabis intake and tolerated by consumers; doses that reach $0.3 mg/kg start to cause unpleasant side-effects, while doses of $0.49 mg/kg produce serious adverse effects (convulsions) that require hospital treatment.…”

Section: Drug Preparation and Animal Dose Determinationmentioning

confidence: 99%

“…and D 9 -THC (0.01-6 mg/kg i.p.) did not cause major neurological changes in the range of doses studied (Vigolo et al, 2015). Therefore, we conducted the behavioral analysis of sensorimotor responses starting 15 min after JWH-018 or D 9 -THC administration.…”

Section: Major Neurological Changesmentioning

confidence: 99%

“…JWH-018 (naphthalen-1-yl-(1-pentylindol-3-yl)methanone) is the first synthetic cannabinoid ever reported through the Early Warning System on Drugs and marketed as ''Spice'' and ''herbal blend'' for its psychoactive effects (European Monitoring Centre for Drugs and Drug Addiction, 6 March 2009, Uchiyama et al, 2010). JWH-018 binds murine, rat and human cannabinoid CB 1 /CB 2 receptors in the low nanomolar range (Huffman et al, 1994;Wiley et al, 1998;Vigolo et al, 2015) showing approximately a fourfold increased activity at CB 1 and about a 10-fold increased affinity at CB 2 receptors compared with (À)-D 9 -THC or Dronabinol Ò (D 9 -THC) (Auwarter et al, 2009). Clinical reports provided by the European Monitoring Centre for Drugs and Drug Addiction (6 March 2009) and by the Italian Early Warning System of the Drug Policies Department (DPA; http://www.allertadroga; http://www.dronet.org/) highlight a number of serious side effects induced by the consumption of JWH-018, such as headache, vomiting, paranoia, tachycardia, seizures, panic attacks, psychosis and hallucinations (Lapoint et al, 2011;Every-Palmer, 2011;de Havenon et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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JWH-018 impairs sensorimotor functions in mice

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Section: Major Neurological Changessupporting

confidence: 60%

Section: Discussionmentioning

confidence: 92%

Section: Drug Preparation and Animal Dose Determinationmentioning

confidence: 99%

Section: Major Neurological Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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JWH-018 impairs sensorimotor functions in mice

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Targeted and non‐targeted metabolite identification of MAM‐2201 in human, mouse, and rat hepatocytes

Kim

Kong

Moon

et al. 2018

Drug Testing and Analysis

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MAM-2201 is a fluorinated naphthoylindole synthetic cannabinoid with potent psychoactive properties that has been detected as an active ingredient in herbal incense blends. To gain a greater understanding of MAM-2201 metabolism and to compare its metabolic fate in humans with those in animals, the metabolism of MAM-2201 in human, mouse, and rat hepatocytes was investigated using liquid chromatography-high-resolution mass spectrometry combined with targeted and non-targeted metabolite profiling approaches. Nineteen phase I metabolites (M1-M19) reported previously in human liver microsomes and 13 novel metabolites were identified in human, mouse, and rat hepatocytes: 1 phase I metabolite (M20) and 12 phase II metabolites including 6 glucuronides (G1-G6), 1 sulfate (S1), and 5 glutathione (GSH) conjugates (GS1-GS5) of MAM-2201 metabolites. G3 was human-specific, but M20, G1, G2, and 5 GSH conjugates were rat-specific, indicating species-related differences in MAM-2201 metabolism. The findings in the present study can be useful for the experimental design and assessment of metabolism-mediated toxic risk of MAM-2201.

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The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent‐4en and but‐3en analogues including MDMB‐4en‐PINACA

Krotulski

Cannaert

Stove

et al. 2020

Drug Testing and Analysis

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A new class of synthetic cannabinoids has emerged as new psychoactive substances (NPS). Similar in structure to JWH‐022, these substances contain alkene modifications to the tail region of the synthetic cannabinoid core structure, and nomenclature denotes these new analogues as pent‐4en or but‐3en species. Internationally, two analogues from this new series recently emerged: MDMB‐4en‐PINACA and MMB‐4en‐PICA. Previously, data regarding activity and potential toxicity were not available. In vitro assessment of cannabinoid receptor 1 (CB1) activation via the β‐arrestin 2 recruitment was studied for three (3) pent‐4en analogues, one (1) but‐3en analogue, and one (1) principal metabolite. MDMB‐4en‐PINACA (2.47 nM, 239%), MDMB‐4en‐PICA (11.5 nM, 302%), and MDMB‐3en‐BINACA (14.3 nM, 286%) were highly potent and efficacious (comparison: JWH‐018, 25.3 nM, 100%), while the potencies of MMB‐4en‐PICA and MDMB‐4en‐PINACA 3,3‐dimethylbutanoic acid were markedly lower. Modifications to core and tail structural features (i.e., indole vs. indazole) led to relatively small differences in potency, while changes among the head region led to larger differences. Sample‐mining and data‐mining conducted on toxicology samples led to the identification of MDMB‐4en‐PINACA in 25 forensic toxicology cases, including postmortem and impaired driving investigations, with case details and limited histories described herein. Moderate geographical distribution of MDMB‐4en‐PINACA was noted in the United States with emergence in the Northeast, Midwest, South, and West regions. Results from toxicology testing paired with case history show the potential for MDMB‐4en‐PINACA to cause or contribute to impairment or death. Forensic scientists, public health and public safety officials, law enforcement, clinicians, medical examiners, and coroners should consider involvement of emergent synthetic cannabinoids in their work and that new analogues containing an alkene tail can retain similar or increased potency and toxicity.

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Novel halogenated derivates of JWH-018: Behavioral and binding studies in mice

Cited by 83 publications

References 51 publications

JWH-018 impairs sensorimotor functions in mice

JWH-018 impairs sensorimotor functions in mice

Targeted and non‐targeted metabolite identification of MAM‐2201 in human, mouse, and rat hepatocytes

The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent‐4en and but‐3en analogues including MDMB‐4en‐PINACA

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