Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σR/TMEM97 ligands.

Sigma-2 receptor (σR/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σR/TMEM97. Especially, 4 analogs showed K values ranging from 0.38 to 5.1 nM for σR/TMEM97 with no or low affinity for sigma-1 receptor (σR). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σR/TMEM97 antagonists according to current understanding. The σR/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σR/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.