Brain levels and relative potency of 1,2-dimethylheptyl analog of delta1-tetrahydrocannabinol in mice

D K Lawrence, Roger Guy Pertwee, Edward W. Gill, J M Piper

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Unlabelled and tritium-labelled (sp. act. 373 mCi/m-mole) forms of the 1,2-dimethylheptyl analogue of ¿1-tetrahydrocannabinol (¿1-DMHP) were prepared as incompletely separated mixtures of threo- and erythro-isomers. The n-heptyl analogue (n-hep-tyl-¿1-THC), was also prepared, and this compound, and samples of ¿1-DMHP containing different proportions of threo- and erythro-isomers. were compared with ¿1-THC using the mouse ring “catalepsy” test. n-Heptyl-¿1-THC was found to be twice as active as ¿1-THC (95 per cent confidence limits 1 and 3): the two isomers of ¿1-DMHP were shown, within the limits of the assay, to possess equal activity, giving a mean potency ratio of 12. The duration of action of both drugs did not differ from that of ¿1-THC. Brain and blood levels of ¿1-DMHP and its metabolites were measured at various times after injection with 3H-¿1-DMHP (0.1 mg/kg) and were compared with the corresponCling levels of ¿1-THC and its metabolites. The major metabolite in the mouse of ¿1-DMHP was isolated from an in vitro mouse liver preparation, and was identified as 7-hydroxy-¿1-DMHP. The brain levels of this metabolite and ¿1-DMHP itself correlated equally well with the behavioural effect, and showed that the higher activity of ¿1-DMHP is not due to metabolic or distribution effects, as both the amount of 7-hydroxy metabolite relative to the parent, and that, in spite of its greater lipid solubility, the fraction of the injected dose which reached the brain were lower than for ¿1-THC. It was concluded that the differences in the potencies of ¿1-THC and ¿1-DMHP in producing behavioural changes in the mouse are due to differences in activity at the site of action.
Original languageEnglish
Pages (from-to)3017-3027
Number of pages11
JournalBiochemical Pharmacology
Issue number21
Publication statusPublished - 1974


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