Synthesis and Pharmacological Activities in Mice of Halogenated Δ^9-Tetrahydrocannabinol Derivatives

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概要

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• Seven halogenated derivatives of Δ^9-tetrahydrocannabinol (Δ^9-THC, 1) substituted on the aromatic ring at the 2 and/or 4 position, 2 (4)-fluoro- (2), 2,4-difluoro- (3), 2-chloro- (4), 2-bromo- (5), 2,4-dibromo- (6), 2-iodo- (7) and 2,4-diiodo-Δ^9-THC (8) were synthesized and pharmacological effects such as catalepsy, anticonvulsant effects, hypothermia, pentobarbital-induced sleep prolongation and locomotor activity evaluated by intracerebroventricular (i.c.v., 25 μg/head) and intravenous (i.v., 5 or 10 mg/kg) injections in mice. The cataleptogenic effects of 2 and 5 were about three-quarters and two-thirds, respectively, compared to those of 1 (i.v.), though other derivatives were much less active (i.c.v. and i.v.) 2 (for clonic seizures) exhibited a significant prolongation of seizure latency induced by pentylenetetrazol (i.v.). Hypothermic effects of monohalogenated derivatives were comparable to 1 when administered by i.v. injection, whereas the effects of dihalogenated derivatives of 1 were attenuated. In contrast, 3 and 8 exhibited a significant hyperthermic effect in mice. In synergy with pentobarbital, 4 and 5 exhibited a significant prolongation of sleeping time by 1.6- and 1.8-fold, respectively, compared with control (32.4±2.5 min), although other derivatives did not affect significantly the sleeping time (i.c.v.). However, by i.v. injection, 2,4,5 and 7 significantly prolonged pentobarbital-induced sleeping time and reduced locomotor activity. The sleep prolonging effects of 2,4 and 7 (10 mg/kg, i.v.) were as potent as that of 1 (5 mg/kg, i.v.). 5 and 7 were the most potent derivatives among the synthetic cannabinoids examined in the present study. These results indicate that halogenation of 1 leads to modification of the pharmacological profile of THC.

• 社団法人日本薬学会の論文
• 1998-09-15

著者

• YAMAMOTO IKUO

  Department of Laboratory Medicine, Miyazaki Medical College

• 景山 節

  京大・霊長類研・生化学

• Yamamoto Ikuo

  Department Of Hygienic Chemistry School Of Pharmaceutical Sciences Kyushu University Of Health And W

• 宇佐見 則行

  九州保健福祉大学薬学部衛生薬学講座 九州保健福祉大学qol研究機構

• Usami Noriyuki

  九州保健福祉大学 薬学部

• Kimura Toshiyuki

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• Watanabe Kazuhito

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• Usami Noriyuki

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• 宇佐見 則行

  北陸大・薬

• KOBANA Kiyofumi

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• YOSHIDA Hisatoshi

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• YOSHIMURA Hidetoshi

  Department of Food and Nutrition, Nakamura Gakuen University

• Yamamoto Ikuo

  北陸大学 薬 衛化

• Yamamoto Ikuo

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• YAMAMOTO IKUO

  Hygienic Chemistry

• Kimura T

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• 景山 節

  京都大学霊長類研究所人類進化モデル研究センター

• 景山 節

  京大・霊長研

• Usami N

  Gifu Pharmaceutical Univ. Gifu Jpn

• Kimura Toshiyuki

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Watanabe Kazuhito

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Watanabe Kazuhito

  Department Of Chemistry And Chemical Engineering Faculty Of Engineering Yamagata University

• Yoshimura Hidetoshi

  Department Of Food And Nutrition Nakamura Gakuen University

• Yoshimura Hidetoshi

  Faculty Of Pharmaceutical Sciences Kyushu University(present):department Of Food And Nutrition Nakam

• Kimura T

  Department Of Medicinal Chemistry Center For Frontier Research In Medicinal Science 21st Century Coe

• Yoshida H

  Lab. Of Food & Nutritional Sciences Dep. Of Nutritional Sci. Kobe-gakuin Univ.

• Yoshimura H

  Faculty Of Pharmaceutical Sciences Kyushu University(present):department Of Food And Nutrition Nakam

• Yamamoto I

  Hygienic Chemistry

• Yoshida Hiromi

  Department Of Nutritional Science Kobe Gakuin University

• Watanabe Kazuhito

  Faculty Of Pharmaceutical Sciences Kyushu University

• Yoshimura Hidetoshi

  Department Of Food And Nutrition Nakamura Gakuen

• Kobana Kiyofumi

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Yamamoto Ikuo

  Department Of Bioapplied Chemistry Faculty Of Engineering Osaka City University

• Kimura T

  Peptide Inst. Inc. Minoh Jpn

• 吉村 英敏

  Department of Nutritional Science, Kobe Gakuin University

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