Discriminative stimulus effects and receptor binding of enantiomeric pairs of cannabinoids in rats and pigeons; A comparison

The cannabimimetic activity of two enantiomeric pairs of compounds structurally different from the classical cannabinoids was evaluated in rats and pigeons, trained to discriminate between the presence and absence of (- )-delta-9-tetrahydrocannabinol (THC). One pair of enantiomers [compounds (+)- HU-249 and (-)-HU-250] has a 5-membered oxygen-containing benzofuran ring; the second pair [(+)-HU-253 and (-)-HU-254] does not have an oxygen- containing ring. The onset of cannabimimetic activity was slower, and duration of action was longer for the test compounds than for THC. HU-250 exhibited cannabimimetic activity with a potency similar to THC in both species; HU-249 was 22 times less active than THC. The pattern of response rate and THC-like responding obtained with HU-249 were dissociated; THC-like responding occurred during the later test intervals when suppression of response rate was reduced. HU-250 bound to the cannabinoid receptor with a K(i) of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a K(i) of 28.3 μM. The triacetate enantiomers, HU-253 and HU- 254, occasioned THC-like responding in both species, HU-254 being about 4.5 times less potent than THC and 3 to 4 times more potent than HU-253. In binding, HU-253 was also less potent than HU-254. The corresponding triols were considerably more potent than the acetates; (-)-HU-256 had a K(i) of 198 nM, whereas (+)-HU-255 had a K(i) of 43.8 nM, comparable to that of THC.