Divergent Cytotoxic and Metabolically Stimulative Functions of Sigma-2 Receptors: Structure-Activity Relationships of 6-Acetyl-3(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79) Derivativess
Divergent Cytotoxic and Metabolically Stimulative Functions of Sigma-2 Receptors: Structure-Activity Relationships of 6-Acetyl-3(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79) Derivativess
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DOI：
10.1124/jpet.118.253484
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发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Bowen, Wayne D.
中科院分区：
文献类型：
--
作者：
Nicholson, Hilary E.;Alsharif, Walid F.;Bowen, Wayne D.
Sigma-2 受体最近被鉴定为 TMEM97，与癌症和神经退行性疾病有关。结构不同的 sigma-2 受体配体可诱导肿瘤细胞死亡，将 sigma-2 受体与细胞凋亡途径联系起来。最近，我们报道 sigma-2 受体还可以刺激糖酵解标志，其作用与癌细胞的促生存功能和上调一致。与经典 sigma-2 拮抗剂 SN79 相关的化合物观察到细胞凋亡和代谢刺激作用。在这里，我们研究了一系列 6-取代的 SN79 类似物，以评估控制这些不同效应的结构决定因素。核心 SN79 结构的苯并恶唑酮环上的取代导致高亲和力 sigma-2 受体配体 (K-i = 0.56-17.9 nM)，用 N-甲基取代杂环氧（产生 N-甲基苯并咪唑酮）通常会降低 sigma-1 亲和力，而硫取代（产生苯并噻唑酮）会在两种亚型上赋予高亲和力，从而降低亚型选择性。用 COCH3、NO2、NH2 或 F 取代 6 位会产生无细胞毒性的配体。其中五种配体诱导代谢活性增加，通过人 SK-N-SH 神经母细胞瘤细胞中 MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四唑）减少的增加来测量，进一步支持 sigma-2 受体在代谢中的作用。用 6-异硫氰酸酯取代产生了 sigma-2 选择性配体，并且不可逆地与 sigma-2 受体结合，但不与 sigma-1 受体结合。这些配体在急性和连续治疗时均诱导细胞死亡（EC50=7.6-32.8μM），表明不可逆的受体结合在细胞毒性中发挥作用。这些配体将有助于进一步研究 sigma-2 受体的这些不同作用。
Sigma-2 receptors, recently identified as TMEM97, have been implicated in cancer and neurodegenerative disease. Structurally distinct sigma-2 receptor ligands induce cell death in tumor cells, linking sigma-2 receptors to apoptotic pathways. Recently, we reported that sigma-2 receptors can also stimulate glycolytic hallmarks, effects consistent with a prosurvival function and upregulation in cancer cells. Both apoptotic and metabolically stimulative effects were observed with compounds related to the canonical sigma-2 antagonist SN79. Here we investigate a series of 6-substituted SN79 analogs to assess the structural determinants governing these divergent effects. Substitutions on the benzoxazolone ring of the core SN79 structure resulted in high-affinity sigma-2 receptor ligands (K-i = 0.56-17.9 nM), with replacement of the heterocyclic oxygen by N-methyl (producing N-methylbenzimidazolones) generally decreasing sigma-1 affinity and a sulfur substitution (producing benzothiazolones) imparting high affinity at both subtypes, lowering subtype selectivity. Substitution at the 6-position with COCH3, NO2, NH2, or F resulted in ligands that were not cytotoxic. Five of these ligands induced an increase in metabolic activity, as measured by increased reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in human SK-N-SH neuroblastoma cells, further supporting a role for sigma-2 receptors in metabolism. Substitution with 6-isothiocyanate resulted in ligands that were sigma-2 selective and that irreversibly bound to the sigma-2 receptor, but not to the sigma-1 receptor. These ligands induced cell death upon both acute and continuous treatment (EC50 = 7.6-32.8 mu M), suggesting that irreversible receptor binding plays a role in cytotoxicity. These ligands will be useful for further study of these divergent roles of sigma-2 receptors.