Discovery of fused heterocyclic carboxamide derivatives as novel α7-nAChR agonists: Synthesis, preliminary SAR and biological evaluation

The alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of alpha 7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of alpha 7 nAChR. Particularly, compounds 10a and 10e showed significantly higher E-max than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 mu M and E-max of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as alpha 4 beta 2 and alpha 3 beta 4 nAChR. 10a evoked alpha 7-like currents that were inhibited by MLA and enhanced in the presence of the alpha 7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel alpha 7-nAChR agonists. (C) 2019 Elsevier Masson SAS. All rights reserved.