Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation

The alpha 7 nicotinic acetylcholine receptor (nAChR) silent agonists, able to induce receptor desensitization and promote the alpha 7 metabotropic function, are emerging as new promising therapeutic anti-inflammatory agents. Herein, we report the structure-activity relationship investigation of the archetypal silent agonist NS6740 (1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)-phenyl)-furan-2-yl)methanone) (1) to elucidate the ligand-receptor interactions responsible for the alpha 7 silent activation. In this study, NS6740 fragments 11-16 and analogs 17-32 were designed, synthesized, and assayed on human alpha 7 nAChRs expressed in Xenopus laevis oocytes with two-electrode voltage clamping experiments. All together the structural portions of NS6740 were critical to engender its peculiar activity profile. The diazabicyclic nucleus was essential but not sufficient for inducing alpha 7 silent activation. The central hydrogen-bond acceptor core and the aromatic moiety were crucial for promoting prolonged alpha 7 receptor binding and sustained desensitization. Compounds 13 and 17 were efficacious partial agonists. Compounds 12, 21, 23-26, and 30 strongly desensitized alpha 7 nAChR and therefore may be of interest for additional investigation of inflammation responses. We gained key structural information useful for further silent agonist development. (C) 2020 Elsevier Masson SAS. All rights reserved.