Systematic asymmetric analog synthesis of fluspidine, a σ1 receptor ligand, to improve ligand affinity

[摘要] Fluspidine is a high affinity ligand of the sigma 1 receptor. To further improve the ligand affinity, fluspidine analogs were systematically synthesized and screened herein. To design the modified ligand analogs, a docking simulation of the protein-ligand complex structure was examined. By using the developed synthetic strategy involving asymmetric catalytic 1,4-reduction of alpha,beta-unsaturated carboxylic esters catalyzed by a chiral cobalt complex, 20 candidates of modified fluspidines were synthesized. The structure-activity relationships showed the development of a hybridized modified fluspidine. In addition, the inhibitory rate could be improved from 45% to 71%. This result demonstrates the importance of the development of a new synthetic method towards improving the ligand performance by providing a series of analogs. (C) 2021 Published by Elsevier Ltd.

[发布日期] 2021-11-23

[关键词] sigma 1-Receptor ligand;Fluspidine;SAR;Asymmetric 1,4-reduction;Co complex