824960-03-4

Cannabinoid analogues that exhibit specificity for the CB2 cannabinoid receptor are provided. The analogues are 1-methoxy-, 1-deoxy-11-hydroxy- and 11-hydroxy-1-methoxy-Δ8-tetrahydrocannabinols and 1-alkyl-3(1-naphthoyl)indoles. The compounds are useful for the treatment of pain (especially pain resulting from inflammation) and cancer (especially glioma tumors).

The synthesis and pharmacology of 47 1-alkyl-3-(1-naphthoyl)indoles (R = C3H7 and C5H11, R′ = H and CH3) is described. Naphthoyl substituents include 4- and 7-alkyl groups, plus 2, 4, 6, and 7-methoxy groups. Three of these compounds are highly selective CB2 receptor agonists. In an effort to improve indole-based CB2 cannabinoid receptor ligands and also to develop SAR for both the CB1 and CB2 receptors, 47 indole derivatives were prepared and their CB1 and CB2 receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1- naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB2 receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPγS assays indicated that JWH-151 is a full agonist at CB2, while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1- naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB1 receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB1 receptor.