Identification of quinoline-based compounds with dual activity against CysLT1R and GPBAR1

Pharmacological therapy based on dual receptor modulators represents an attractive opportunity for the modulation of the same cellular process by acting on different pathways. In this work, the discovery of new ligands with dual activity against two membrane receptors is presented: the cysteinyl leukotriene receptor 1 (CysLT1R) and the G protein coupled bile acid receptor 1 (GPBAR1). The novel quinoline series has been designed starting from the structure of REV5901, the first dual compound reported, with antagonist activity towards CysLT1R and agonist towards GPBAR1 (1). Molecular modeling studies, including molecular docking, molecular dynamics (MD) and metadynamics (MetaD) simulations, followed by biological assays, clarified the binding mode of the most active compounds in the two GPCRs receptors, underlining the unprecedented structural basis for future drug design studies. The newly synthetized compounds show therapeutic potential in the treatment of colitis and other inflammatory processes.