Identification of cysteinyl-leukotriene-receptor 1 antagonists as ligands for the bile acid receptor GPBAR1

Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G-Protein-Coupled Bile Acid Receptor 1

“…Docking calculations of 1 – 15 in the GPBAR1 model showed remarkably similar binding modes, with the quinoline group positioned in the amphipathic pocket between transmembrane helices (TM) 3 and 5, interacting with residues known to participate to ligand/GPBAR1 binding like Tyr89 3.29 , Asn93 3.33 , Phe96 3.36 , and Trp237 6.48 (superscripts refer to Ballesteros–Weinstein numbering) (e.g., see Figure ). ,,− On the other hand, docking calculations in the cryo-EM structures did not lead to convergent results, either involving residues known to contribute to ligand binding; therefore, they were not further considered in the study. In CysLT 1 R, compounds 1 – 15 showed similar binding modes where the quinoline moiety is placed in the pocket formed by TM3, TM4, and TM5, directed toward the bilayer-embedded lateral entrance of the receptor (e.g., see Figure ).…”

“…The latter is another class A GPCR activated by secondary bile acids and highly expressed in the intestine, gall bladder, brown adipose tissue, muscles, and immune cells. − Targeting GPBAR1 with agonist molecules has demonstrated being a valid strategy to contrast hepatic inflammation, steatohepatitis, biliary diseases, and metabolic syndromes . In particular, we reported that REV5901 has positive effects in a mouse model of colitis with reduced levels of CysLTs, CysLT 1 R, and cyclooxygenase 1 and 2 in a GPBAR1-dependent manner . These data should be further analyzed considering that the CysLT 1 R antagonist montelukast has shown effect against colitis-associated colon carcinogenesis and inflammation .…”

“…The discovery of the first CysLT 1 R antagonists, namely, montelukast, zafirlukast, and pranlukast (Figure ), has greatly impacted on the treatment of asthma and respiratory morbidities and many more CysLT 1 R antagonists have been developed and tested in preclinical and clinical trials . Among these, we have recently reported α-pentyl-3-[2-quinolinylmethoxy] benzyl alcoholREV5901 (Figure )as the first compound endowed with dual activity as CysLT 1 R antagonist and agonist of the G-protein-coupled bile acid receptor 1 (GPBAR1) . The latter is another class A GPCR activated by secondary bile acids and highly expressed in the intestine, gall bladder, brown adipose tissue, muscles, and immune cells. − Targeting GPBAR1 with agonist molecules has demonstrated being a valid strategy to contrast hepatic inflammation, steatohepatitis, biliary diseases, and metabolic syndromes .…”

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

“…The GPBAR1 homology model reported in D’Amore et al ( D’Amore et al, 2014 ) was employed for docking calculations. The receptor was prepared as in Biagioli et al ( Biagioli et al, 2020b ).…”

“…Following this general concept, we have recently envisaged in REV5901, a well-characterized CysLT 1 R antagonist, a privileged chemical scaffold for the development of dual CysLT 1 R antagonists/GPBAR1 agonists ( Biagioli et al, 2020b ), reporting the first family of derivatives improved in their synthetic accessibility and in their pharmacokinetic profiles ( Fiorillo et al, 2021 ).…”