ECRO XXVI Athens – “Sensorial Chemistry”: functional characterization and structure activity relationship understanding of OR5K1 and OR2AG1 allow to design and synthetize new selective compounds”

ChemCom has deorphanized more than 120 human ORs relying on (i) an efficient proprietary screening system and (ii) libraries of thousands of odorant compounds. Accordingly, ChemCom is currently identifying and characterizing new modulating molecules (enhancers or blockers) and novel odorant compounds for the whole range of hORs. We previously made structure-activity relationship (SAR) studies on two unrelated and well known hORs1, 2, 3,4, OR5K1 and OR2AG1, highly expressed in the whole olfactory mucosa5 and we wanted to go one step further by linking in vitro profile of the best identified ligands of these 2 hORs to their in vivo organoleptic properties. If we were able, among a large set of commercially available compounds (>120), to identify ligands displaying good selectivity for OR5K1 compared to OR2AG1, or dual acting OR5K1 – OR5AG1, we could not identify compounds displaying a good selectivity for OR2AG1 versus OR5K1. Thus, by making an in depth analysis on SARs established on both hORs, subtle differences on aza heterocycles were identified enabling us to design ligands likely to display good to remarkable selectivity for OR2AG1 versus OR5K1. After chemical synthesis and in vitro characterization, those compounds effectively display the expected selectivity: • allowing the sensorial assessment of OR2AG1, OR5K1 and dual OR1AG1/OR5K1 ligands. • Aiming to demonstrate that “Sensorial Chemistry” might allow to modulate the olfactory properties of volatile organic compounds Download Pdf