Design, synthesis, and structure–activity relationships of diindolylmethane derivatives as cannabinoid CB2 receptor agonists. Issue 3 (27th November 2022)

• Record Type: Journal Article
• Authors: Mahardhika, Andhika B.; Ressemann, Anastasiia; Kremers, Sarah E.; Gregório Castanheira, Mariana S.; Schoeder, Clara T.; Müller, Christa E.; Pillaiyar, Thanigaimalai
• Is Part Of: Archiv der Pharmazie. Volume 356:Issue 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-27
• Subjects: agonist -- allosteric -- cannabinoid receptors -- DIM -- structure–activity relationship; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200493
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: 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‐1 H ‐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‐1 H ‐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‐((1 H ‐indol‐3‐yl)methyl)−4‐methyl‐1 H ‐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. Abstract : A series of diindolylmethane (DIM) derivatives were synthesized and evaluated for their affinities and functional potencies at the human cannabinoid (CB)1 and CB2 receptors. Compound 46 was found to be the most potent CB2 receptor agonist of the series. Compound 44 showed higher potency in β‐arrestin than in cAMP accumulation assays, while 149 displayed a 19‐fold bias for the G protein pathway. DIM and its analogs act as allosteric CB2 receptor agonists.