Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands

Sigma-2 receptor (s2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective sigma(2) ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective sigma(2) 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 sigma R-2/TMEM97. Especially, 4 analogs showed K-i values ranging from 0.38 to 5.1 nM for sigma R-2/TMEM97 with no or low affinity for sigma-1 receptor (sigma R-1). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative sigma R-2/TMEM97 antagonists according to current understanding. The s2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded sigma R-2/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

Efforts to discover new and selective sigma(2) ligands have led to the identification of tetrahydroisoquinolino-2-alkyl phenone analogs with moderate to potent affinity and selectivity for sigma R-2/TMEM97, which may have potential therapeutic implications for neurodegenerative diseases.