Pharmacological evaluation of halogenated delta 8-THC analogs.
-(-)-5'-Bromo-delta 8-THC, (-)-5'-trifluoromethyl-delta 8-THC, (-)-5'-iodo-delta 8-THC, (-)-5'-fluoro-delta 8-THC, (-)-11-fluoro-delta 8-THC and (-)-2-iodo-delta 8-THC were synthesized and evaluated in male ICR mice for their effects on sedation, temperature, catalepsy and antinociception following intravenous injection. The analogs were also tested for relative affinities for cannabinoid binding sites derived from rat cortex membranes, using [3H] CP-55,940 as the tritiated ligand. The results showed that the 5'-bromo, 5'-iodo and 5'-trifluoromethyl analogs were 2-40 times more potent than (-)-delta 8-THC in all biological tests, while the 5'-fluoro and 11-fluoro derivatives were less active. With the 2-iodo analog, a 12-fold separation was observed between antinociception and sedation, pointing to the importance of the side chain orientation in determining cannabinoid activity and to the possible involvement of more than one cannabinoid receptor site. The pharmacological data closely paralleled the data obtained from the binding assay.
Charalambous
A
A
Department of Medicinal Chemistry, School of Pharmacy, University of Connecticut, Storrs 06269-2092.
Lin
S
S
Marciniak
G
G
Banijamali
A
A
Friend
F L
FL
Compton
D R
DR
Martin
B R
BR
Makriyannis
A
A
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D003511:Cyclohexanols / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects
D000700:Analgesics; D003511:Cyclohexanols; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C035731:delta-8-tetrahydrocannabinol; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol