Design, synthesis and SAR exploration of 3-substituted 1,2,3,4-tetrahydroisoquinoline (THIQ) as sigma ligands

Sigma receptors (σ₁R and σ₂R) are emerging therapeutic targets implicated in neurodegenerative, oncological, and psychiatric disorders. This study explores the design, synthesis, and SAR of 3-substituted tetrahydroisoquinoline (THIQ) ligands for σRs. A two-step synthesis was performed using EDC/HOBt-mediated amide coupling followed by Boc-deprotection. After fully characterized each final compound the Ki values were determined through PDSP screening. These findings provide a framework for optimizing THIQ-based sigma ligands for therapeutic applications.