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 Ki of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a Ki of 28.3 microM. 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 Ki of 198 nM, whereas (+)-HU-255 had a Ki of 43.8 nM, comparable to that of THC.
Järbe
T U
TU
Department of Psychology, Faculty of Social Sciences, University of Uppsala, Sweden.
Hiltunen
A J
AJ
Mathis
D A
DA
Hanŭs
L
L
Breuer
A
A
Mechoulam
R
R
D000818:Animals; D010856:Columbidae; D004193:Discrimination Learning / Q000187:drug effects*; D013759:Dronabinol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol