The search for selective ligands for the CB2 receptor

Following the identification of the CB2 receptor several groups explored th e development of selective ligands for this receptor which occurs principal ly in the periphery. This led to the discovery that two cannabimimetic indo les, 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholino]ethyl)-5-methoxyin dole (L768242) and 2-methyl-1-propyl-3-(1-naphthoyl)indole (JWH-015) have h igh affinity for the CB2 receptor with low affinity for the CB1 receptor. S hortly thereafter two 1- IPI methoxy-Delta(8)-THC analogues, 1-methoxy-Delt a(8)-THC-DMH (L759633) and 1-methoxy-Delta(9(11))-THC-DMH (L759656), were a lso found to have high affinity for the CB2 receptor and very little affini ty for the CBI receptor. Almost simultaneously two 1-deoxy-Delta(8)-THC ana logues, 1-deoxy-11-hydroxy-Delta(8)-THC-DMH (JWH-051) and 1-deoxy-Delta(8)- THC-DMH (JWH-057) were reported to have high affinity for the CB1 receptor, but even greater affinity for the CB2 receptor. These discoveries gave ris e to a concerted effort by Huffman and co-workers to explore the structure- activity relationships (SAR) at CB2 of cannabimimetic indoles and 1-deoxy-D elta(8)-THC analogues. These efforts have resulted in the synthesis and pha rmacological evaluation of a number of derivatives of 3-(1-naphthoyl)indole s and 1-deoxy-Delta(8)-THC analogues with various side chains. This review will describe the current status of the results of these studies and discus s the SAR for both these classes of ligands.