Discovery of Novel Benzamide-Based Sigma-1 Receptor Agonists with Enhanced Selectivity and Safety.

ABSTRACT: Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to its role in neuroprotection and neuroinflammation. Building upon our previously identified S1R ligand (compound 1), we designed and synthesized six novel benzamide derivatives through pharmacomodulation to optimize affinity, selectivity, and safety profiles. Among these, compound 2 demonstrated superior S1R affinity, improved selectivity over the sigma-2 receptor (S2R), and favorable ADME properties, including enhanced perme

SUBMITTER: Carato P 

PROVIDER: S-EPMC12430443 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature