PHARMACOLOGY AND STEREOSELECTIVITY OF STRUCTURALLY NOVEL CANNABINOIDS IN MICE

Abstract

The pharmacological effects of three stereoisomeric pairs of structurally novel cannabinoids were tested after i.v. administration in mice for depression of spontaneous activity and the production of hypothermia, antinociception and catalepsy. The (-)-enantiomers were as much as 770 times more potent than .DELTA.9-6a,10a-trans-tetrahydrocannabinol and were 7 to 2000 times more potent than their respective (+)-enantiomers. The order of potency for cannabinoid-induced effects was spontaneous activity > antinociception > hypothermia .gtoreq. catalepsy. Levonantradol was active between 0.123 to 1.5 mg/kg, whereas dextronantradol, its (+)-enantiomer was inactive. (-)-CP 55,244 and (-)-CP55,940 (see scheme 1) analogs which lack the dihydropyran ring were 5 to 775 times more potent than .DELTA.9-6a,10.alpha.-trans-tetrahydrocannabinol and 30 to 2000 times more potent than their respective (+)-enantiomers. Some separation of effects was demonstrated with (+)-CP 55,243 and (-)-CP 56,667 which were inactive in producing hypothermia and catelepsy but were active in the spontaneous activity and tail-flick procedures. The high degree of enantioselectivity and potency of these nonclassical cannaboinoids are indicative of a highly specific mechanism of action such as a receptor.