Article
Author: Haydo, Alicia S. ; Schmachtel, Tessa ; Kaiser, Astrid ; Zaliani, Andrea ; Nevermann, Sheila ; Gribbon, Philipp ; Wolf, Markus ; Moroz, Yurii S. ; Merk, Daniel ; Sisignano, Marco ; Schermeng, Tina ; Offermanns, Stefan ; Heering, Jan ; Ivanov, Vladimir V. ; Proschak, Ewgenij ; Ehrler, Johanna H. M. ; Höfner, Georg ; Alnouri, Mohamad Wessam ; Steinhilber, Dieter ; Marinescu, Beatrice ; Mathes, Marius ; Schubert-Zsilavecz, Manfred ; Rieger, Michael A. ; Hernandez-Olmos, Victor ; Beck-Sickinger, Annette G.
G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)-d-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.