title: Novel halogenated derivates of JWH-018: Behavioral and binding studies in mice.
abstract: JWH-018 is a synthetic CB1 and CB2 agonist illegally marketed as products named "Spice" or "herbal blend" for its psychoactive effects which are much higher than those produced by cannabis. In the last year, the European Monitoring Centre for Drugs and Drug Addiction reported to the Italian National Early Warning System the seizure of plant material containing new halogenated derivatives of JWH-018 (JWH-018 Cl and JWH-018 Br). The present study aimed to investigate the in vitro and in vivo activity of these two new synthetic cannabinoids in mice. In vitro competition binding experiments performed on mouse and human CB1 receptors revealed a high affinity and potency of the halogenated compounds. Synthetic cannabinoids (0.01-6 mg/kg i.p.) impaired motor activity and induced catalepsy in mice and their effects were more severe with respect to those evoked by Δ(9)-THC. Moreover, they increased the mechanical and thermal pain threshold and induced a marked hypothermia. It is interesting to note that whereas high doses of JWH-018 cause seizures, myoclonia and hyperreflexia, the halogenated compounds, in particular JWH-018Br, were less effective. Behavioral and neurological changes were prevented by the selective CB1 receptor antagonist AM 251. These data demonstrate for the first time that JWH-018 Cl and JWH-018 Br act similarly to JWH-018 while inducing less convulsive episodes and myoclonias. These data support the hypothesis that the halogenated compounds may have been introduced onto market to produce similar intoxicating effects as JWH-018 while causing less side effects.
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vigolo
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ossato
authors.affiliation: Collaborative Center for the Italian National Early Warning System, Drug Policies Department, Presidency of the Council of Ministers, Italy; Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Italian National Early Warning System, Drug Policies Department, Presidency of the Council of Ministers, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rimondo
authors.affiliation: Italian National Early Warning System, Drug Policies Department, Presidency of the Council of Ministers, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Seri
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Varani
authors.affiliation: Italian National Early Warning System, Drug Policies Department, Presidency of the Council of Ministers, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Serpelloni
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy; Center for Neuroscience and Istituto Nazionale di Neuroscienze, Italy; Collaborative Center for the Italian National Early Warning System, Drug Policies Department, Presidency of the Council of Ministers, Italy. Electronic address: m.marti@unife.itm.
authors.forename: M
authors.initials: M
authors.lastname: Marti
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002375:Catalepsy / Q000139:chemically induced; D003412:Cricetulus; D054879:Halogenation; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012021:Reflex, Abnormal / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced
chemical_list: C000605613:1-(5-bromopentyl)-3-(1-naphthoyl)indole; C000605612:1-(5-chloropentyl)-3-(1-naphthoyl)indole; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D007211:Indoles; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C103505:AM 251; C552597:1-pentyl-3-(1-naphthoyl)indole
keywords: AM 251 (PubChem CID: 2125); CB(1) receptor; JWH-018; JWH-018 (PubChem CID: 10382701); JWH-018 Br; JWH-018 Cl; Synthetic cannabinoids; Δ(9)-THC; Δ(9)-THC (PubChem CID: 16078)