Recent Advances in the Development of Selective Ligands for the Cannabinoid CB2 Receptor
John W. Huffman and Karla-Sue C. Marriott
Affiliation: H. L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973,USA.
Two subtypes of the mammalian cannabinoid receptor have been identified and successfully cloned since 1990. The CB1 receptor is primarily located in the central nervous system and the CB2 receptor is almost exclusively expressed in cells of the immune system. The CB1 and CB2 receptors are both G-protein coupled receptors and are involved in the inhibition of adenylate cyclase. The CB2 receptor is of particular importance due to its involvement in signal transduction in the immune system, making it a potential target for therapeutic immune intervention. A number of these selective ligands are derivatives of traditional dibenzopyran based cannabinoids. These include the very recently synthesized (2R)- 1-methoxy-3-(2-methylbutyl)-Δ8-THC (JWH-359) which has a 224 fold selectivity for the CB2 receptor, readily comparable to the well known 1-deoxy-3-(1,1-dimethylbutyl)-Δ8-THC (JWH-133) which has 200 fold selectivity for the CB2 receptor. Several 9-hydroxyhexahydrocannabinols have also been synthesized and are found to be selective high affinity ligands for the CB2 receptor. These are 1-deoxy-9β-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, Ki = 2.7 nM) and 1-deoxy-9β-hydroxy-dimethylpentylhexahydrocannabinol (JWH-300, Ki = 5.3 nM). CB2 selective cannabimimetic indoles include 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholine]ethyl)-5-methoxyindole (L768242), (R)-3- (2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) and 1-propyl-2-methyl-3-(1-naphthoyl) indole (JWH-015), which exhibit significant selectivity for the CB2 receptor coupled with weak affinity for the CB1 receptor. Bristol-Meyer Squibb has produced a phenylalanine derived cannabimimetic indole which possesses high CB2 affinity (Ki = 8 nM) and very low affinity for the CB1 receptor (Ki = 4000 nM). This review will discuss the current advances and recent results in the structure-activity relationships (SAR) of selective ligands for the cannabinoid CB2 receptor.
Keywords: Cannabinoids, structure-activity relationships, CB2 receptor, CB2 selective ligands, aminoalkylindoles
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