Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate- induced inflammation and skin tumour promotion in mice Jun’ichi Nakajima a , Dai Nakae a and Ken Yasukawa b a Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo and b School of Pharmacy, Nihon University, Funabashi, Chiba, Japan Keywords anti-inflammatory effect; anti-tumour-promoting agent; synthetic cannabinoids; 12-O-tetradecanoylphorbol-13-acetate; two-stage carcinogenesis Correspondence Jun’ichi Nakajima, Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Sinjuku-ku, Tokyo 169-0073, Japan. E-mail: Junichi_Nakajima@member.metro.tokyo.jp Received December 18, 2012 Accepted April 11, 2013 doi: 10.1111/jphp.12082 Abstract Objectives 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 metropoli- tan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Further- more, 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. Key findings 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. Introduction During our careful surveillance of unregulated, illegal drugs in Japan, numerous cannabimimetic analogues have been found and identified. [1–8] Most of the identified compounds have been categorized as indole derivatives, [9–15] leading to the idea that they may have anti-inflammatory activity, similar to that of the well-known anti-inflammatory indole derivative, indometacin. Cannabinoids are classified into three types: (1) cannabinoids derived from the plant Can- nabis Sativa L.; [16] (2) endogenous cannabinoids, anandam- ide [17] and 2-arachidonoylglycerol; [18] and (3) synthetic cannabinoids. [19] All of these compounds bind to G-protein coupled cannabinoid receptors, CB1 and CB2. Because CB1 and CB2 are overexpressed in certain cancers, [20,21] it has been suggested that cannabinoids may possess an anti- tumour activity. In fact, the synthetic cannabinoids JWH- 015 and Win55,212-2 have been shown to inhibit the growth and metastasis of non-small cell lung cancer by affecting CB1 and CB2. [22] Furthermore, another synthetic cannabinoid, JWH-133, has been reported to inhibit the growth and angiogenesis of skin tumours also via the activation of cannabinoid receptors. [23] It has not been well investigated, however, whether and how cannabinoids affect inflammation and carcinogenesis. In this context, the present study was conducted to assess effects of synthetic And Pharmacology Journal of Pharmacy Research Paper © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 65, pp. 1223–1230 1223 Downloaded from https://academic.oup.com/jpp/article/65/8/1223/6132910 by guest on 23 July 2022