Synthesis and pharmacological activities in mice of halogenated delta 9-tetrahydrocannabinol derivatives.
Seven halogenated derivatives of delta 9-tetrahydrocannabinol (delta 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-delta 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 micrograms/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.
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
N
N
Usami
K
K
Kobana
H
H
Yoshida
T
T
Kimura
K
K
Watanabe
H
H
Yoshimura
I
I
Yamamoto
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006213:Hallucinogens / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D006219:Halogens / Q000737:chemistry*; D007036:Hypothermia, Induced; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
D006213:Hallucinogens; D006219:Halogens; D013759:Dronabinol