N-ethyl-17(R,S)-methyl-(6aR,10aR)-Δ8-tetrahydrocannabinol-18-oic amide: Brain pharmacokinetics in mice, triglyceride/ phospholipid partitioning and generalization to the discriminative stimulus properties of Δ9-THC in rats

Abstract 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 Δ 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 Δ 9 -THC (ED 50 = 1.8 mg/kg) and its vehicle, the amide was generalized to the training drug, being five times less potent (Ed 50 = 8.7 mg/kg) than Δ 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.