In this work we report the structure–affinity relationships, binding properties, and metabolic stability studies of a series of benzo[d]thiazol-2(3H)one as sigma receptor (σR) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (SN56), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound 12 had low nanomolar affinity for the σ₁R (K_i = 7.2 nM) and moderate preference (61-fold) over the σ₂R. In vitro metabolic stability studies showed a slight improvement of the metabolic stability for 7–12, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of 12 suggested that the N-methyl group of the adamantyl moiety is a major site of metabolism.

中文翻译：

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探索 1-金刚烷胺作为新合成苯并[d]噻唑-2(3 H)one σ 受体配体中代谢不稳定氮杂环庚烷环的替代胺部分

在这项工作中，我们报告了一系列作为 σ 受体 (σR) 配体的苯并[ d ]噻唑-2(3 H )one的结构-亲和力关系、结合特性和代谢稳定性研究。具体来说，为了提高我们的先导化合物（SN56）环胺片段的代谢稳定性，代谢不稳定的氮杂环被 1-金刚烷胺部分取代。在合成的类似物中，化合物12对 σ ₁ R具有低纳摩尔亲和力( K _i  = 7.2 nM) 和对 σ ₂ R 的适度偏好（61 倍）。体外代谢稳定性研究显示代谢稳定性略有改善对于7 12，即使观察到大鼠肝微粒体中的广泛代谢。此外，12 的代谢软点鉴定表明金刚烷基部分的N-甲基是代谢的主要位点。