| Abstract
| - The separation of the mood-altering effects ofcannabinoids from their therapeutic effects hasbeen long sought. Results reported here for a series of C-9analogs of the cyclic ether O,2-propano-Δ8-tetrahydrocannabinol(O,2-propano-Δ8-THC) point to the C-1 positionin classicalcannabinoids as a position for which CB2 subtypeselectivity occurs within the cannabinoidreceptors. O,2-Propano-11-nor-Δ8-THC,O,2-propano-Δ9,11-THC,O,2-propano-9-oxo-11-nor-hexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), andO,2-propano-9α- and O,2-propano-9β-OH-11-nor-HHC were synthesized and evaluated in radioliganddisplacement assays foraffinity at the CB1 and CB2 receptors and inthe mouse vas deferens in vitro assay and themouse tetrad in vivo assay for cannabinoid activity.Evaluation of binding affinity at the CB1and CB2 receptors revealed that each compound possesses amodest increased affinity for theCB2 receptor. Analogs which contained an oxygenattached to C-9 (i.e., oxo and hydroxyderivatives) showed the highest affinity and selectivity forCB2 (for O,2-propano-9-oxo-11-nor-HHC, Ki(CB1) = 90 nM,Ki(CB2) = 23 nM, selectivityratio 3.9; for O,2-propano-9β-OH-11-nor-HHC, Ki(CB1) = 26 nm,Ki(CB2) = 5.8 nM, selectivityratio 4.5). Each compound was found toproduce a dose-dependent inhibition of electrically-evoked contractionsof the mouse isolatedvas deferens when administered at submicromolar concentrations.This inhibition could readilybe prevented by the selective CB1 cannabinoid receptorantagonist SR-141716A. The analogsexhibited unique in vivo profiles withO,2-propano-Δ9,11-THC exhibitingantinociception withreduced activity in three other in vivo measures andO,2-propano-9β-OH-HHC exhibiting lackof dose responsiveness in all measures. The CB2selectivities of the O,2-propano analogs maybe due to differences in solvation/desolvation that occur when theligands enter the CB1 vsCB2 binding site. Alternatively, the CB2selectivities may be the result of an amino acid changefrom a hydrogen bond-accepting residue in CB1 to a hydrogenbond-donating residue in CB2.
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