N-Ethyl-17(R,S)-methyl-(6aR,10aR)-delta 8-tetrahydrocannabinol-18-oic amide. Brain pharmacokinetics in mice, triglyceride/phospholipid partitioning and generalization to the discriminative stimulus properties of delta 9-THC in rats.
The title compound, designed as a model for the affinity moiety of a cannabinoid affinity gel was synthesized in tritiated form (sp. act. 7.27 mCi/mmole). To validate the affinity approach to isolate the putative THC receptor, the properties of the amide were studied. Upon i.p. injection in mice the amide reaches peak brain levels of 0.13% of the total dose after 15 min. Following i.v. injection, maximal brain concentrations of 1.9% are observed at 5 min. Compared to delta 9-THC, which distributes almost equally between triglyceride and phospholipid phases (51:49) the amide exhibits a strong preference for phospholipids (5:95) that can be interpreted as high relative membrane affinity. In rats trained in a water maze to discriminate between i.p. injections of 3 mg/kg delta 9-THC (ED50 = 1.8 mg/kg) and its vehicle, the amide was generalized to the training drug, being five times less potent (ED50 = 8.7 mg/kg) than delta 9-THC. This demonstration of cannabis-like activity indicates that the amide retains affinity to the postulated receptor and justifies the choice for the affinity ligand.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004193:Discrimination Learning / Q000187:drug effects*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D005795:Generalization, Stimulus / Q000187:drug effects*; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D010743:Phospholipids; D051381:Rats; D012995:Solubility; D014280:Triglycerides
D008024:Ligands; D010743:Phospholipids; D014280:Triglycerides; D013759:Dronabinol; C046890:N-ethyl-17-methyl-delta(8)-tetrahydrocannabinol-18-oic amide