Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, United States.
Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, United States.
Eur J Med Chem. 2022 Dec 5;243:114696. doi: 10.1016/j.ejmech.2022.114696. Epub 2022 Aug 28.
Initially associated with cancer diagnosis and therapy, the sigma 2 receptor (σR) has recently been implicated in several disorders of the central nervous system (CNS). It remained a poorly characterized target until we identified it as the transmembrane protein 97 (TMEM97). As part of a program to identify novel compounds that bind with high affinity and selectivity to σR/TMEM97 relative to the sigma 1 receptor (σR) and other CNS proteins, we employed a scaffold simplification strategy to design novel sets of piperazine-substituted aminotetralins based on analogous norbenzomorphans that we previously developed. JVW-1601 was identified as a reference aminotetralin analog that had high affinity (K = 5.5 nM) and selectivity (36-fold) for σR/TMEM97 versus σR. An expanded investigation of structure-activity relationships (SAR) in several structural regions of this compound was conducted, and among the ligands thus prepared, many had K values < 20 nM for σR/TMEM97 and selectivities of >20-fold versus σR. Structural features that enhance σR/TMEM97 affinity and selectivity were identified, leading to an optimized compound having a high σR/TMEM97 affinity (K of 4.5 nM) and 366-fold selectivity relative to σR. Significantly, during the course of this work we discovered JVW-1625, which enabled the isolation and identification of σR as TMEM97 and resolved a question that had eluded researchers for decades. Computational docking studies for selected aminotetralins suggest they adopt similar poses upon binding to σR/TMEM97, engaging in highly conserved salt bridges with Asp29 and cation-π interactions with Tyr150. Collectively, these studies show that aminotetralins are useful tool compounds for studying the mechanism and function of σR/TMEM97.
最初与癌症诊断和治疗相关联，sigma 2 受体（σR）最近被牵连到中枢神经系统（CNS）的几种疾病中。直到我们将其鉴定为跨膜蛋白 97（TMEM97），它才成为一个特征描述不佳的靶点。作为一项旨在确定与 sigma 1 受体（σR）和其他中枢神经系统蛋白相比，与 sigma 2 受体（σR）/跨膜蛋白 97（TMEM97）具有高亲和力和选择性的新型化合物的项目的一部分，我们采用了支架简化策略来设计基于我们之前开发的类似诺苯吗啡的新型哌嗪取代的氨基四氢萘系列。JVW-1601 被鉴定为具有高亲和力（K = 5.5 nM）和选择性（相对于 σR 为 36 倍）的氨基四氢萘类似物。对该化合物几个结构区域的结构-活性关系（SAR）进行了广泛的研究，在所制备的配体中，许多配体对 σR/TMEM97 的 K 值均<20 nM，相对于 σR 的选择性均>20 倍。确定了增强 σR/TMEM97 亲和力和选择性的结构特征，从而得到一种优化的化合物，对 σR/TMEM97 具有高亲和力（K 为 4.5 nM）和相对于 σR 的 366 倍选择性。重要的是，在这项工作的过程中，我们发现了 JVW-1625，这使得能够分离和鉴定 σR 为 TMEM97，并解决了一个困扰研究人员数十年的问题。对选定的氨基四氢萘进行的计算对接研究表明，它们在与 σR/TMEM97 结合时采用类似的构象，与 Asp29 形成高度保守的盐桥，并与 Tyr150 形成阳离子-π 相互作用。总的来说，这些研究表明氨基四氢萘是研究 σR/TMEM97 机制和功能的有用工具化合物。
