{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T13:21:21Z","timestamp":1777036881110,"version":"3.51.4"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T00:00:00Z","timestamp":1369094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Tokyo Metropolitan Government"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key findings<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first report indicating the structure\u2013activity 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jphp.12082","type":"journal-article","created":{"date-parts":[[2013,5,22]],"date-time":"2013-05-22T02:23:01Z","timestamp":1369189381000},"page":"1223-1230","source":"Crossref","is-referenced-by-count":16,"title":["Structure-dependent inhibitory effects of synthetic cannabinoids against 12-<i>O<\/i>-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice"],"prefix":"10.1093","volume":"65","author":[{"given":"Jun'ichi","family":"Nakajima","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dai","family":"Nakae","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Yasukawa","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nihon University, Funabashi, Chiba, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,5,21]]},"reference":[{"key":"2021022517584321000_jphp12082-bib-0001","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1248\/cpb.57.439","article-title":"Identification of a cannabinoid analog as a new type of designer drug in a herbal product","volume":"57","author":"Uchiyama","year":"2009","journal-title":"Chem Pharm Bull"},{"key":"2021022517584321000_jphp12082-bib-0002","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11419-009-0069-y","article-title":"Identification of a cannabimimetic indole as a designer drug in a herbal product","volume":"27","author":"Uchiyama","year":"2009","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0003","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s11419-010-0100-3","article-title":"Identification and quantitation of two cannabimimetic phenylacetylindoles JWH-251 and JWH-250, and four cannabimimetic naphthoylindoles JWH-081, JWH-015, JWH-200, and JWH-073 as designer drugs in illegal products","volume":"29","author":"Uchiyama","year":"2011","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0004","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11419-010-0101-2","article-title":"Identification and quantitation of cannabimimetic compound JWH-250 as an adulterant in products obtained via the Internet","volume":"29","author":"Nakajima","year":"2011","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0005","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11419-011-0108-3","article-title":"Identification and quantitation of two benzoylindoles AM-694 and (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone, and three cannabimimetic naphthoylindoles JWH-210, JWH-122 and JWH-019 as adulterants found in illegal products obtained via the Internet","volume":"29","author":"Nakajima","year":"2011","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0006","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s11419-011-0114-5","article-title":"Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl)-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S]GTP\u03b3S binding assays","volume":"29","author":"Nakajima","year":"2011","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0007","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s11419-011-0130-5","article-title":"Identification and quantitation of two new naphthoylindole drugs-of-abuse, (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202) and (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone, with other synthetic cannabinoids in unregulated \u2018herbal\u2019 products circulated in Tokyo area","volume":"30","author":"Nakajima","year":"2012","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0008","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/s11419-012-0136-7","article-title":"Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products","volume":"30","author":"Uchiyama","year":"2012","journal-title":"Forensic Toxicol"},{"key":"2021022517584321000_jphp12082-bib-0009","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1016\/j.bmcl.2005.06.008","article-title":"1-pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles","volume":"15","author":"Huffman","year":"2005","journal-title":"Bioorg Med Chem Lett"},{"key":"2021022517584321000_jphp12082-bib-0010","volume-title":"Cannabimimetic indole derivatives","author":"Makriyannis","year":"2007"},{"key":"2021022517584321000_jphp12082-bib-0011","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/jlcr.720","article-title":"Regioselective F-18 radio labeling of AM694, a CB1 Cannabinoid Receptor Ligand","volume":"46","author":"Willis","year":"2003","journal-title":"J Label Compd Radiopharm"},{"key":"2021022517584321000_jphp12082-bib-0012","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.bmc.2004.09.050","article-title":"Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists","volume":"13","author":"Huffman","year":"2005","journal-title":"Bioorg Med Chem"},{"key":"2021022517584321000_jphp12082-bib-0013","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0376-8716(99)00152-0","article-title":"Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding","volume":"60","author":"Aung","year":"2000","journal-title":"Drug Alcohol Depend"},{"key":"2021022517584321000_jphp12082-bib-0014","doi-asserted-by":"publisher","first-page":"e21917","DOI":"10.1371\/journal.pone.0021917","article-title":"Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity","volume":"6","author":"Brents","year":"2011","journal-title":"PLoS ONE"},{"key":"2021022517584321000_jphp12082-bib-0015","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S0022-3565(24)37496-8","article-title":"Structure-activity relationships of indole and pyrrole-derived cannabinoids","volume":"285","author":"Wiley","year":"1998","journal-title":"J Pharmacol Exp Ther"},{"key":"2021022517584321000_jphp12082-bib-0016","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1021\/ja01062a046","article-title":"Isolation, structure and partial synthesis of an active constituent of hashish","volume":"86","author":"Gaoni","year":"1964","journal-title":"J Am Chem Soc"},{"key":"2021022517584321000_jphp12082-bib-0017","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.1470919","article-title":"Isolation and structure of a brain constituent that binds to the cannabinoid receptor","volume":"258","author":"Devane","year":"1992","journal-title":"Science"},{"key":"2021022517584321000_jphp12082-bib-0018","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0006-2952(95)00109-D","article-title":"Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors","volume":"50","author":"Mechoulam","year":"1995","journal-title":"Biochem Pharmacol"},{"key":"2021022517584321000_jphp12082-bib-0019","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S0960-894X(01)80155-4","article-title":"Design, synthesis and pharmacology of cannabimimetic indoles","volume":"4","author":"Huffman","year":"1994","journal-title":"Bioorg Med Chem Lett"},{"key":"2021022517584321000_jphp12082-bib-0020","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cancergencyto.2006.06.014","article-title":"Overexpression of cannabinid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma","volume":"171","author":"Xu","year":"2006","journal-title":"Cancer Genet Cytogenet"},{"key":"2021022517584321000_jphp12082-bib-0021","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1158\/1535-7163.MCT-09-0448","article-title":"Synthetic cannabinoid receptor agonists inhibit tumour growth and metastasis of breast cancer","volume":"8","author":"Qamri","year":"2009","journal-title":"Mol Cancer Ther"},{"key":"2021022517584321000_jphp12082-bib-0022","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1158\/1940-6207.CAPR-10-0181","article-title":"Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis","volume":"4","author":"Preet","year":"2011","journal-title":"Cancer Prev Res (Phila)"},{"key":"2021022517584321000_jphp12082-bib-0023","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1172\/JCI200316116","article-title":"Inhibition of skin tumour growth and angiogenesis in vivo by activation of cannabinoid receptors","volume":"111","author":"Casanova","year":"2003","journal-title":"J Clin Invest"},{"key":"2021022517584321000_jphp12082-bib-0024","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1211\/jpp\/61.08.0009","article-title":"Relative inhibitory activity of bile aids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two-stage carcinogenesis","volume":"61","author":"Yasukawa","year":"2009","journal-title":"J Pharm Pharmacol"},{"key":"2021022517584321000_jphp12082-bib-0025","doi-asserted-by":"crossref","first-page":"E2199","DOI":"10.1096\/fj.06-6638fje","article-title":"Cannabinoid receptors as novel targets for the treatment of melanoma","volume":"20","author":"Bl\u00e1zquez","year":"2006","journal-title":"FASEB J"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjphp.12082","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjphp.12082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/academic.oup.com\/jpp\/article-pdf\/65\/8\/1223\/36387224\/jphp12082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jpp\/article-pdf\/65\/8\/1223\/36387224\/jphp12082.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T10:53:29Z","timestamp":1746010409000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/65\/8\/1223-1230\/6132910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,21]]},"references-count":25,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2013,5,21]]},"published-print":{"date-parts":[[2013,7,10]]}},"URL":"https:\/\/doi.org\/10.1111\/jphp.12082","relation":{},"ISSN":["2042-7158","0022-3573"],"issn-type":[{"value":"2042-7158","type":"electronic"},{"value":"0022-3573","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,8]]},"published":{"date-parts":[[2013,5,21]]}}}