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

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 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 σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases. [Display omitted] •Fifteen tetrahydroisoquinoline derivatives were synthesized and evaluated for their affinities for σ1R and σ2R/TMEM97.•Four analogs, 9, 12, 15 and 18, showed high affinity and selectivity for σ2R/TMEM97.•Analogs 9, 12, 15 and 18 did not affect the intracellular Ca2+ and were not cytotoxic against MCF-7 cancer cells.•Analogs 9, 12, 15 and 18 are considered to be putative σ2R/TMEM97 antagonists.•Analogs 9, 12, 15 and 18 may potentially be useful for the treatment of neurodegenerative diseases.