Synthesis and Pharmacological Evaluation in Mice of Halogenated Cannabidiol Derivatives

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Six halogenated derivatives of cannabidiol (CBD, 1) substituted on the aromatic ring at the 3' and/or 5' position, 3'-chloro- (2), 3', 5'-dichloro- (3), 3'-bromo- (4), 3', 5'-dibromo- (5), 3'-iodo- (6) and 3', 5'-diiodo-CBD (7) were synthesized and their pharmacological effects of barbiturate-induced sleep prolongation, anticonvulsant effects and locomotor activity were evaluated by intravenous (i.v.) injection in mice. 2 (10 mg/kg, i.v., 69±10 min) significantly prolonged pentobarbital-induced sleeping time by 3.1-fold, compared to control (22±2 min), although other 1 derivatives used did not significantly affect the sleeping time. 2,4 and 6 (10 mg/kg, i.v.) significantly prolonged hexobarbital-induced sleeping time by 2.0-, 2.0- and 2.3-fold, respectively, compared with control (52±5 min). On the other hand, 1 and all halogenated derivatives did not significantly prolong barbital-induced sleeping time. The monohalogenated derivatives, 2,4 and 6 were able to prolong pentobarbital and hexobarbital-induced sleeping time, although the dihalogenated derivatives, 3,5 and 7 did not exhibit a prolongation of the sleeping time. All halogenated derivatives of 1 except for brominated derivatives (2,3,6,7) tended to prolong tonic seizure latency induced by pentylenetetrazol. 1 and its halogenated derivatives did not exhibit any prolongation of seizure latency induced by picrotoxin or strychnine. Maximal electroshock test demonstrated that 1 and 4 exhibited almost the same potency in their anticonvulsant effects, although other 1 derivatives 2,3,5,6 and 7 did not show significant effect up to a dose of 63 mg/kg, i.v. The ED_<50> values (mg/kg, i.v.) of 1 and 4 were 38 and 44,respectively. 1 and 4 also showed anticonvulsant effect in minimal and maximal electroshock-threshold tests. 2,4 and 6 tended to decrease the total distance (horizontal activity) and number of rearings (vertical activity) of mice, whereas 3,5 and 7 tended to increase the number of rearings. However, the effects of all derivatives were not statistically significant from the control. 2 and 4 were the most potent derivatives on pharmacological activities among the synthetic cannabinoids examined in the present study. These results indicate that monohalogenation of 1 leads to some modification of the pharmacological profile of CBD.
社団法人日本薬学会の論文
1999-11-15

Synthesis and Pharmacological Evaluation in Mice of Halogenated Cannabidiol Derivatives

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