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

Identification of Cysteinyl-leukotriene-receptor 1 antagonists as ligands for the bile acid receptor GPBAR1. Biochem Pharmacol. 2020 Apr 21;:113987 Authors: Biagioli M, Carino A, Marchianò S, Roselli R, Di Giorgio C, Bordoni M, Fiorucci C, Sepe V, Conflitti P, Limongelli V, Distrutti E, Baldoni M, Zampella A, Fiorucci S Abstract The cysteinyl leukotrienes (CysLTs), i.e. LTC4, LTD4 and LTE4, are a family of proinflammatory agents synthesized from the arachidonic acid. In target cells, these lipid mediators bind to the cysteinyl leukotriene receptors (CysLTR), a family of seven transmembrane G-protein coupled receptors. The CysLT1R is a validated target for treatment of pulmonary diseases and several selective antagonists for this receptor, including montelukast, zafirlukast and pranlukast, have shown effective in the management of asthma. Nevertheless, others CysLT1R antagonists, such as the alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV5901), have been extensively characterized without reaching sufficient priority for clinical development. Since drug reposition is an efficient approach for maximizing investment in drug discovery, we have investigated whether CysLT1R antagonists might exert off-target effects. In the report we demonstrate that REV5901 interacts with GPBAR1, a well characterized cell membrane receptor for secondary bile acids. REV5901 transactivates GPBAR1 in GPBAR1-transfected cells with an EC50 of 2.5 µM ...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research