Design, synthesis, and structure-activity relationships of diindolylmethane derivatives as cannabinoid CB₂ receptor...

3,3'-Diindolylmethane (DIM), a natural product-derived compound formed upon ingestion of cruciferous vegetables, was recently described to act as a partial agonist of the anti-inflammatory cannabinoid (CB) receptor subtype CB₂ . In the present study, we synthesized and evaluated a series of DIM derivatives and determined their affinities for human CB receptor subtypes in radioligand binding studies. Potent compounds were additionally evaluated in functional cAMP accumulation and β-arrestin recruitment assays. Small substituents in the 4-position of both indole rings of DIM were beneficial for high CB₂ receptor affinity and efficacy. Di-(4-cyano-1H-indol-3-yl)methane (46, PSB-19837, EC₅₀ : cAMP, 0.0144 µM, 95% efficacy compared to the full standard agonist CP55,940; β-arrestin, 0.0149 µM, 67% efficacy) was the most potent CB₂ receptor agonist of the present series. Di-(4-bromo-1H-indol-3-yl)methane (44, PSB-19571) showed higher potency in β-arrestin (EC₅₀ 0.0450 µM, 61% efficacy) than in cAMP accumulation assays (EC₅₀ 0.509 µM, 85% efficacy) while 3-((1H-indol-3-yl)methyl)-4-methyl-1H-indole (149, PSB-18691) displayed a 19-fold bias for the G protein pathway (EC₅₀ : cAMP, 0.0652 µM; β-arrestin, 1.08 µM). DIM and its analogs act as allosteric CB₂ receptor agonists. These potent CB₂ receptor agonists have potential as novel drugs for the treatment of inflammatory diseases.