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

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 beta-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 mu M, 95% efficacy compared to the full standard agonist CP55,940; beta-arrestin, 0.0149 mu M, 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 beta-arrestin (EC50 0.0450 mu M, 61% efficacy) than in cAMP accumulation assays (EC50 0.509 mu M, 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 mu M; beta-arrestin, 1.08 mu M). 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.

Automated summary

The study synthesized a series of DIM derivatives and evaluated their affinities and efficacies for human CB receptor subtypes. The compound di-(4-cyano-1H-indol-3-yl)methane showed the highest potency as a CB2 receptor agonist and has potential as a novel drug for inflammatory diseases.