Design, synthesis and biological activities of piperidine-spirooxadiazole derivatives as α7 nicotinic receptor antagonists

alpha: 7 nicotinic acetylcholine receptors (nAChRs) expressed in the nervous and immune systems have been suggested to play important roles in the control of inflammation. However, the lack of antagonist tools specifically inhibiting alpha 7 nAChR impedes the validation of the channel as therapeutic target. To discover a selective alpha 7 antagonist, we started a pharmacophore-based virtual screening and identified a piperidine-spirooxadiazole derivative T761-0184 that acts as a alpha 7 antagonist. A series of novel piperidine-spirooxadiazole derivatives were subsequently synthesized and evaluated using two-electrode voltage clamp (TEVC) assay in Xenopus oocytes. Lead compounds from two series inhibited alpha 7 with their IC50 values ranging from 3.3 mu M to 13.7 mu M. Compound B10 exhibited alpha 7 selectivity over other alpha 4 beta 2 and alpha 3 beta 4 nAChR subtypes. The analysis of structure-activity relationship (SAR) provides valuable insights for further development of selective alpha 7 nAChR antagonists. (C) 2020 Elsevier Masson SAS. All rights reserved.