TMEM97 and cancer: Its antagonistprofile toward the σ1R was discovered more than 20years ago, along with its in vitro and invivo anticancer properties toward several cancer types.41−47 In 2011, Schläger et al. reported a series of spirocyclicpyranopyrazoles with high σ1R affinity and selectivitytoward the σ2R, α1, α2, 5-HT1AR, and the 5-HT-transporter.48 Two chemically and pharmacologically distincthigh-affinity σ1R ligands named 4-IBP (agonist orinverse agonist) and PD144418 (antagonist) were used to obtain theabove-mentioned first crystal structures of the human σ1R (Figure 2).49,50