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.
Bioorg Chem. 2024 Apr;145:107191. doi: 10.1016/j.bioorg.2024.107191. Epub 2024 Feb 10.
The sigma 2 receptor (σR), which was recently identified as the transmembrane protein 97 (TMEM97), is increasingly attracting interest as a possible therapeutic target for indications in neuroscience. Toward identifying novel modulators of σR/TMEM97, we prepared a collection of benzoxazocine, benzomorphan, and methanobenzazepine ligands related to the known bioactive norbenzomorphans DKR-1677, FEM-1689, and EES-1686 and determined their K values for σR/TMEM97 and the sigma 1 receptor (σR). The σR/TMEM97 binding affinities and selectivities relative to σR of these new benzoxazocine, benzomorphan, and methanobenzazepine analogs are lower, often significantly lower, than their respective norbenzomorphan counterparts, suggesting the spatial orientation of pharmacophoric substituents is critical for binding to the two proteins. The benzoxazocine, benzomorphan, and methanobenzazepine congeners of DKR-1677 and FEM-1689 tend to be weakly selective for σR/TMEM97 versus σR, whereas EES-1686 derivatives exhibit the greatest selectivity, suggesting the size and/or nature of the substituent on the nitrogen atom of the scaffold may be important for selectivity. Computational docking studies were performed for the 1S,5R-and 1R,5S-enantiomers of DKR-1677, FEM-1689, and EES-1686 and their benzoxazocine, benzomorphan, and methanobenzazepine counterparts. These computations predict that the protonated amino group of each ligand forms a highly conserved salt bridge and a H-bonding interaction with Asp29 as well as a cation-π interaction with Tyr150 of σR/TMEM97. These electrostatic interactions are major driving forces for binding to σR/TMEM97 and are similar, though not identical, for each ligand. Other interactions within the well-defined binding pocket also tend to be comparable, but there are some major differences in how the hydrophobic aryl groups of various ligands interact with the protein surface external to the binding pocket. Overall, these studies show that the orientations of aryl and N-substituents on the norbenzomorphan and related scaffolds are important determinants of binding affinity of σR/TMEM97 ligands, and small changes can have significant effects upon binding profiles.
最近被鉴定为跨膜蛋白 97（TMEM97）的 sigma 2 受体（σR），作为神经科学领域各种适应症的潜在治疗靶点，正日益受到关注。为了鉴定 σR/TMEM97 的新型调节剂，我们制备了一系列与已知生物活性的 norbenzomorphans DKR-1677、FEM-1689 和 EES-1686 相关的苯并恶唑嗪、苯并吗啡烷和甲苯并氮杂䓬配体，并测定了它们对 σR/TMEM97 和 sigma 1 受体（σR）的 K 值。这些新的苯并恶唑嗪、苯并吗啡烷和甲苯并氮杂䓬类似物对 σR/TMEM97 的 σR 结合亲和力和选择性通常明显低于其相应的 norbenzomorphan 对应物，这表明药效团取代基的空间取向对于与两种蛋白的结合至关重要。DKR-1677 和 FEM-1689 的苯并恶唑嗪、苯并吗啡烷和甲苯并氮杂䓬同系物对 σR/TMEM97 相对于 σR 的选择性较弱，而 EES-1686 衍生物的选择性最大，这表明支架氮原子上取代基的大小和/或性质可能对选择性很重要。对 DKR-1677、FEM-1689 和 EES-1686 的 1S,5R-和 1R,5S-对映异构体及其苯并恶唑嗪、苯并吗啡烷和甲苯并氮杂䓬类似物进行了计算对接研究。这些计算预测，每个配体的质子化氨基形成高度保守的盐桥和与 Asp29 的氢键相互作用以及与 σR/TMEM97 的 Tyr150 的阳离子-π 相互作用。这些静电相互作用是与 σR/TMEM97 结合的主要驱动力，对于每种配体都是相似的，尽管不完全相同。在定义明确的结合口袋内的其他相互作用也往往是可比的，但各种配体的疏水性芳基与结合口袋外部的蛋白质表面的相互作用有一些重大差异。总体而言，这些研究表明，norbenzomorphan 及其相关支架上的芳基和 N-取代基的取向是 σR/TMEM97 配体结合亲和力的重要决定因素，微小的变化会对结合谱产生重大影响。
