3-(1 ',1 '-dimethylbutyl)-1-deoxy-Delta(8)-THC and related compounds: Synthesis of selective ligands for the CB2 receptor

The synthesis and pharmacology of 15 1-deoxy-Delta(8)-THC analogues, severa l of which have high affinity for the CB2 receptor, are described. The deox y cannabinoids include 1-deoxy-11-hydroxy-Delta(8)-THC (5), 1-deoxy-Delta(8 )-THC (6), 1-deoxy-3-butyl-Delta(8)-THC (7), 1-deoxy-3-hexyl-Delta(8)-THC ( 8) and a series of 3-(1',1'-dimethylalkyl)-1-deoxy-Delta(8)-THC analogues ( 2, n= 0-4, 6, 7, where n=the number of carbon atoms in the side chain-2). T hree derivatives (17-19) of deoxynabilone (16) were also prepared. The affi nities of each compound for the CB1 and CB2 receptors were determined emplo ying previously described procedures. Five of the 3-(1',1'-dimethylalkyl)-1 -deoxy-Delta(8)-THC analogues (2, n = 1-5) have high affinity (K-i = < 20 n M) for the CB2 receptor. Four of them (2, n= 1-4) also have little affinity for the CB1 receptor (K-i = > 295 nM). 3-(1',1'-Dimethylbutyl)-1-deoxy-Del ta(8)-THC (2, n = 2) has very high affinity for the CB2 receptor (K-i = 3.4 +/- 1.0 nM) and little affinity for the CB1 receptor (K-i = 677 +/- 132 nM ). (C) 1999 Elsevier Science Ltd. All rights reserved.