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

Abstract

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-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 α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 μM and Emax 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 α4β2 and α3β4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.

• Authors: Yu Xue, Xiaomeng He, Taoyi Yang, Yuxi Wang, Zhenming Liu, Guisen Zhang, Yanxing Wang, Kewei Wang, Liangren Zhang, Lihe Zhang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 182 Pg. 111618 (Nov 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31434041 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Heterocyclic Compounds
• Indolizines
• alpha7 Nicotinic Acetylcholine Receptor
• indolizine

Topics

• Animals
• Dose-Response Relationship, Drug
• Drug Discovery
• Female
• Heterocyclic Compounds (chemical synthesis, chemistry, pharmacology)
• Indolizines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Structure-Activity Relationship
• Xenopus laevis
• alpha7 Nicotinic Acetylcholine Receptor (agonists)