The Search for Selective Ligands for the CB2 Receptor

J.   W.   Huffman

Abstract

Following the identification of the CB2 receptor several groups explored the development of selective ligands for this receptor which occurs principally in the periphery. This led to the discovery that two cannabimimetic indoles, 1-(2,3-dichlorobenzoyl)- 2-methyl-3-(2-[1-morpholino]ethyl)-5-methoxyindole (L768242) and 2-methyl-1-propyl-3-(1-naphthoyl)indole (JWH-015) have high affinity for the CB2 receptor with low affinity for the CB1 receptor. Shortly thereafter two 1- methoxy-Delta 8 -THC analogues, 1-methoxy-Delta 8 -THC-DMH (L759633) and 1-methoxy-Delta 9(11) -THC-DMH (L759656), were also found to have high affinity for the CB2 receptor and very little affinity for the CB1 receptor. Almost simultaneously two 1-deoxy-Delta 8 -THC analogues, 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 CB 2 receptor. These discoveries gave rise to a concerted effort by Huffman and co-workers to explore the structure-activity relationships (SAR) at CB2 of cannabimimetic indoles and 1-deoxy-Delta 8 -THC analogues. These efforts have resulted in the synthesis and pharmacological evaluation of a number of derivatives of 3-(1-naphthoyl)indoles 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 discuss the SAR for both these classes of ligands.

Keywords: Selective Ligands, CB2 Receptor, cannabimimetic indoles, 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholino]ethyl)-5-methoxyindole (L768242)and 2-methyl-1-propyl-3-(1-naphthoyl)indole (JWH-015), methoxy-D8-THC analogues, 1-methoxy-D8-THC-DMH (L759633) and 1-methoxy-D9(11)-THC-DMH (L759656), CB1 receptor, 1-deoxy-D8-THC analogues, 1-deoxy-11-hydroxy-D8-THC-DMH(JWH-051) and 1-deoxy-D8-THC-DMH (JWH-057), structure-activity relationships (SAR), CB2, 1-deoxy-D8-THC analogues, 3-(1-naphthoyl)indoles, 1-deoxy-D8-THC, marijuana (Cannabis sativa L.), Structure, D9-THC, WIN-55,212-2, JWH-015, L768242, Structures of 1-Deoxy- and 1-Methoxy-D8-THC analogues, THC-DMH, BIOASSAY METHODS, Cannabinoid receptor, SR144528 and CP-55,940, CB2 SELECTIVE LIGANDS, Indoles, CB1 and CB2 Affinities, Structures of JWH-018 and 2-methyl-1-morpholinoethyl-3-(1-naphthoyl)indole, Structures of various cannabimimetic indoles, Traditional Cannabinoids