Abstract by Marija Ciba
Succinate receptor 1 (SUCNR1) is a G protein-coupled receptor (GPCR) activated by a small tricarboxylic acid cycle intermediate termed succinate. A growing body of evidence suggests that succinate-SUCNR1 signaling is involved in the development of various undesirable physiological conditions, including inflammation, renal hypertension, and retinal vascularization. Moreover, SUCNR1 has attracted a lot of interest as a likely target for the treatment of liver fibrosis, rheumatoid arthritis, ulcerative colitis, and other inflammatory diseases. Although several potent SUCNR1 ligands have been reported, there is a strong need to develop potent tool compounds to help elucidate the functions of SUCNR1 as well as uncover its full therapeutical potential.
Current knowledge of the structure, signaling, and different physiological implications of SUCNR1 is outlined in Chapter 1. Although most studies suggest that inhibition of SUCNR1 is therapeutically relevant, some studies highlight the benefits of SUCNR1 activation since it exerts anti-inflammatory effects in the central nervous system. Therefore, given the contrasting physiological character of the receptor, both synthetic agonists and antagonists are needed. The tool compounds with activity on both human and rodent receptor orthologues are of particular interest, as they would allow investigation of the receptor in vivo in a more streamlined manner.
Chapter 2 describes the structure activity relationship (SAR) studies of SUCNR1 antagonists with activity on rodent receptor orthologues. Supported by the recently published X-ray structure of SUCNR1, the new molecules were designed based on the reported scaffolds of known antagonists PB-20-OV24 and NF-56-EJ40. While initial efforts were directed towards targeting the mouse receptor orthologue, the design of the subsequent series of analogues was adapted to target the rat receptor orthologue, resulting in the identification of a low-potency antagonist 2.40i with activity on rat SUCNR1.
Chapter 3 outlines the importance and use of fluorescently labeled ligands within the GPCR research field. Initially, a linker and fluorophore two-part library was developed which served as a useful platform for the development of fluorescent ligands for SUCNR1. As a result, a potent fluorescent agonist tracer 3.16 was developed. Furthermore, SAR explorations around the scaffolds presented in Chapter 2, resulted in the identification of a potent fluorescent SUCNR1 antagonist 3.23. Moreover, the spectroscopic characterization of the developed fluorescent tracers uncovered an unexpected fluorescent behavior of 3.16.
Chapter 4 describes the use of the linker and fluorophore two-part library in the development of the fluorescent ligands for other carboxylate-sensing receptors, including free fatty acid receptor 1 (FFA1), FFA4, and GPR84.