Diindolylmethane Derivatives: Potent Agonists of the Immunostimulatory Orphan G Protein-Coupled Receptor GPR84

The
Gi protein-coupled receptor GPR84, which is activated by
(hydroxy)­fatty acids, is highly expressed on immune cells. Recently,
3,3′-diindolylmethane was identified as a heterocyclic, nonlipid-like
GPR84 agonist. We synthesized a broad range of diindolylmethane derivatives
by condensation of indoles with formaldehyde in water under microwave
irradiation. The products were evaluated at the human GPR84 in cAMP
and β-arrestin assays. Structure–activity relationships
(SARs) were steep. 3,3′-Diindolylmethanes bearing small lipophilic
residues at the 5- and/or 7-position of the indole rings displayed
the highest activity in cAMP assays, the most potent agonists being
di­(5-fluoro-1H-indole-3-yl)­methane (38, PSB-15160, EC50 80.0 nM) and di­(5,7-difluoro-1H-indole-3-yl)­methane (57, PSB-16671, EC50 41.3 nM). In β-arrestin assays, SARs were different,
indicating biased agonism. The new compounds were selective versus
related fatty acid receptors and the arylhydrocarbon receptor. Selected
compounds were further investigated and found to display an ago-allosteric
mechanism of action and increased stability in comparison to the lead
structure.