Department of Chemistry, University of Texas at Austin, Austin, TX 78712, United States.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States.
Eur J Med Chem. 2018 May 10;151:557-567. doi: 10.1016/j.ejmech.2018.02.024. Epub 2018 Mar 29.
Substituted norbenzomorphans are known to display high affinity and selectivity for the two sigma receptor (σR) subtypes. In order to study the effects of simplifying the structures of these compounds, a scaffold hopping strategy was used to design several novel sets of substituted isoindolines, tetrahydroisoquinolines and tetrahydro-2-benzazepines. The binding affinities of these new compounds for the sigma 1 (σ1R) and sigma 2 (σ2R) receptors were determined, and some analogs were identified that exhibit high affinity (K ≤ 25 nM) and significant selectivity (>10-fold) for σ1R or σ2R. The preferred binding modes of selected compounds for the σ1R are predicted by modeling studies, and the nature of substituents on the aromatic ring and the nitrogen atom of the bicyclic skeleton appears to affect the preferred binding orientation of σ1R-preferring ligands.
取代的去甲苯并吗啡烷类化合物已知对两种 sigma 受体（σR）亚型具有高亲和力和选择性。为了研究简化这些化合物结构的效果，采用了支架跳跃策略来设计几组新型取代的异吲哚啉、四氢异喹啉和四氢-2-苯并氮杂卓。测定了这些新化合物与 sigma 1（σ1R）和 sigma 2（σ2R）受体的结合亲和力，鉴定出一些具有高亲和力（K≤25nM）和对 σ1R 或 σ2R 显著选择性（>10 倍）的类似物。通过建模研究预测了选定化合物与 σ1R 的优先结合模式，芳香环和双环骨架上的取代基的性质似乎影响了 σ1R 偏好配体的优先结合取向。
