Cannabinoid penetration into mouse brain as determined by ex vivo binding.

We have used an ex vivo binding assay in the mouse to evaluate the brain penetration of cannabinoid receptor ligands. After intraperitoneal or oral administration, the pharmacological activity linked to the compound was assessed by using by [3H]WIN 55212-2 binding on cerebellar membranes. The brain penetration was high for compounds like methanandamide or delta9-tetrahydrocannabinol but poor for synthetic agonists such as (cis)-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-(trans)-4-(3-hydr oxypropyl)cyclohexanol (CP 55940) or, R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-d e]-1,4-benzoxazin-6-yl)(1-napthalenyl)methanone monomethane-sulfonate (WIN 55212-2). After oral administration the duration of action of delta9-tetrahydrocannabinol, methanandamide and WIN 55212-2 is limited and decreased 4 h after administration. The cannabinoid CB1 receptor antagonist: N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1 H-pyrazole-3-carboxamide hydrochloride (SR141716A) exhibited a good brain penetration and a long duration of action.