title: Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice.
abstract: OBJECTIVE
  Whether and how synthetic cannabinoids affect inflammation and carcinogenesis has not been well studied. The present study was thus conducted to assess effects of synthetic cannabinoids on inflammation and carcinogenesis in vivo in mice.
  
  
  METHODS
  Twenty-three analogues of synthetic cannabinoids were isolated from, and identified as adulterants in, illegal drugs distributed in the Tokyo metropolitan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, selected cannabinoids, JWH-018, -122 and -210, were studied for their effects on carcinogenesis induced in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA.
  
  
  RESULTS
  Among cannabinoids, naphthoylindoles mostly exhibited superior inhibitory effects against TPA-induced ear oedema and, especially, JWH-018, -122 and -210 showed potent activity with 50% inhibitory dose (ID50) values of 168, 346 and 542 nm, respectively (an activity corresponding to that of indometacin (ID50 = 908 nm)). Furthermore these three compounds also markedly suppressed the tumour-promoting activity of TPA.
  
  
  CONCLUSIONS
  This is the first report indicating the structure-activity relationships for the anti-inflammatory activity of synthetic cannabinoids on TPA-induced inflammation in mice. Naphthoylindoles, JWH-018, -122 and -210, had the most potent anti-inflammatory activity and also markedly inhibited tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. The present results suggest that synthetic cannabinoids, such as JWH-018, -122 and -210, may be used as cancer chemopreventive agents in the future.
authors.affiliation: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan. Junichi_Nakajima@member.metro.tokyo.jp
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Nakajima
authors.forename: Dai
authors.initials: D
authors.lastname: Nakae
authors.forename: Ken
authors.initials: K
authors.lastname: Yasukawa
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D003043:Cocarcinogenesis; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002186:Cannabinoids; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate
keywords: 12-O-tetradecanoylphorbol-13-acetate; anti-inflammatory effect; anti-tumour-promoting agent; synthetic cannabinoids; two-stage carcinogenesis