Importance of the C-1 Substituent in Classical Cannabinoids to CB2 Receptor Selectivity: Synthesis and Characterization of a Series of O,2-Propano-Δ8-tetrahydrocannabinol Analogs

Authors

Patricia H. Reggio, Kennesaw State UniversityFollow
Tiansheng Wang, Research Triangle Institute
Amy E. Brown, RTI International
Denise N. Fleming, RTI International
Herbert H. Seltzman, RTI InternationalFollow
Graeme Griffin, Aberdeen University
Roger G. Pertwee, Aberdeen University
David R. Compton, Medical College of VirginiaFollow
Mary E. Abood, Medical College of VirginiaFollow
Billy R. Martin, Medical College of VirginiaFollow

Document Type

Article

Publication Date

9-26-1997

Abstract

The separation of the mood-altering effects of cannabinoids from their therapeutic effects has been long sought. Results reported here for a series of C-9 analogs of the cyclic ether O,2-propano-Δ⁸-tetrahydrocannabinol (O,2-propano-Δ⁸-THC) point to the C-1 position in classical cannabinoids as a position for which CB₂ subtype selectivity occurs within the cannabinoid receptors. O,2-Propano-11-nor-Δ⁸-THC, O,2-propano-Δ^9,11-THC, O,2-propano-9-oxo-11-nor-hexahydrocannabinol (O,2-propano-9-oxo-11-nor-HHC), and O,2-propano-9α- and O,2-propano-9β-OH-11-nor-HHC were synthesized and evaluated in radioligand displacement assays for affinity at the CB₁ and CB₂ receptors and in the mouse vas deferens in vitro assay and the mouse tetrad in vivo assay for cannabinoid activity. Evaluation of binding affinity at the CB₁ and CB₂ receptors revealed that each compound possesses a modest increased affinity for the CB₂ receptor. Analogs which contained an oxygen attached to C-9 (i.e., oxo and hydroxy derivatives) showed the highest affinity and selectivity for CB₂ (for O,2-propano-9-oxo-11-nor-HHC, K_i(CB₁) = 90 nM, K_i(CB₂) = 23 nM, selectivity ratio 3.9; for O,2-propano-9β-OH-11-nor-HHC, K_i(CB₁) = 26 nm, K_i(CB₂) = 5.8 nM, selectivity ratio 4.5). Each compound was found to produce a dose-dependent inhibition of electrically-evoked contractions of the mouse isolated vas deferens when administered at submicromolar concentrations. This inhibition could readily be prevented by the selective CB₁ cannabinoid receptor antagonist SR-141716A. The analogs exhibited unique in vivo profiles with O,2-propano-Δ^9,11-THC exhibiting antinociception with reduced activity in three other in vivo measures and O,2-propano-9β-OH-HHC exhibiting lack of dose responsiveness in all measures. The CB₂ selectivities of the O,2-propano analogs may be due to differences in solvation/desolvation that occur when the ligands enter the CB₁ vs CB₂ binding site. Alternatively, the CB₂ selectivities may be the result of an amino acid change from a hydrogen bond-accepting residue in CB₁ to a hydrogen bond-donating residue in CB₂.