Design and Synthesis of Tetrahydropyrrolo[3,4‐c]Pyrazole Sigma‐1 Receptor Ligands

This study presents a series of tetrahydropyrrolo[3,4-c]pyrazole-based compounds designed as sigma-1 receptor (S1R) ligands, focusing on optimizing affinity and reducing off-target effects. We synthesized various derivatives from commercially available precursors and, through radioligand binding assays, assessed their binding affinity for S1R and sigma-2 receptor (S2R). Compound 19 (AD417), containing a benzyl group and an amide substituent, demonstrated notable S1R affinity (Ki=75 nM) with 6-fold selectivity over S2R. Modifications on the pyrrolidine nitrogen were crucial in enhancing receptor interaction, as the protonated nitrogen likely interacts with Glu172 within the S1R binding site. Furthermore, to address hERG potassium ion channel inhibition, a known limitation in S1R drug development, we evaluated compound 19’s cardiotoxicity potential. With an experimental hERG IC50 of 5.8 μM, significantly higher than verapamil's IC50 of 0.41 μM, and haloperidol's IC50 of 0.16 μM, compound 19 showed a safer profile, suggesting a reduced risk of cardiotoxicity. These findings underscore the role of nitrogen accessibility, structural flexibility, and functional group modifications in optimizing S1R ligand interactions and provide a promising foundation for developing safer S1R-targeted therapeutics with minimized hERG-related risks.