Novel cannabinol probes for CB1 and CB2 cannabinoid receptors

The observation that the phenolic hydroxyl of THCs was important for bindin g to the CB1 receptor but not as critical for binding to the CB2 receptor p rompted us to extend this finding to the cannabinol (CBN) series. To study the SAR of CBN analogues, CBN derivatives with substitution at the C-1, C-3 , and C-9 positions were chosen since these positions have played a key rol e in the SAR of THCs. CBN-3-(1',1'-dimethylheptyl) analogues were prepared by sulfur dehydrogenation of Delta(8)-THC-3-(1',1'-dimethylheptyl) analogue s. 9-Substituted CBN analogues were prepared by the standard sulfur dehydro genation of B-substituted Delta(8)-THC analogues (Scheme 1), which in turn were prepared following our previous procedure using selenium dioxide oxida tion of the corresponding Delta(8)-THCs followed by sodium chlorite oxidati on to give the 9-carboxy-Delta(8)-THC derivatives. Il-Hydroxy-CBN analogues were prepared from the corresponding 9-carbomethoxy-CBN analogues by reduc tion with LiAlH4. Deoxy-CBN analogue 14 was prepared from the corresponding Delta(8)-THC analogue 11 by conversion of the phenolic hydroxyl to the pho sphate derivative 12, followed by lithium ammonia reduction to provide the deoxy-as-THC analogue 13, which in turn was dehydrogenated with sulfur to p rovide the deoxy-CBN analogue 14 (Scheme 2). The various analogues were ass ayed for binding both to the brain and the peripheral cannabinoid receptors (CB1 and CB2). We have found that the binding profile differs widely betwe en the CBN and the THC series. Specifically, in the CBN Series the removal of the phenolic hydroxyl decreases binding affinity to both the CB1 and CB2 receptors, whereas in the THC series, CB1 affinity is selectively reduced. Thus, in the CBN series, the selectivity of binding observed with the remo val of the hydroxy group is decreased severalfold as compared to what occur s in the THC series. Generally, high affinity for the CB2 receptor was foun d in analogues when the phenolic hydroxyl was present. The 3-(1',1'-dimethy lheptyl) derivatives were found to have much higher affinities than the CBN analogues, which is in complete agreement with previously reported work by Rhee et al(16).