Intagliata Sebastiano, Agha Hebaalla, Kopajtic Theresa A, Katz Jonathan L, Kamble Shyam H, Sharma Abhisheak, Avery Bonnie A, McCurdy Christopher R
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Department of BioMolecular Science, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
Med Chem Res. 2020 Sep;29(9):1697-1706. doi: 10.1007/s00044-020-02597-2. Epub 2020 Jul 8.
In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[]thiazol-2(3)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound had low nanomolar affinity for the σR ( = 7.2 nM) and moderate preference (61-fold) over the σR. metabolic stability studies showed a slight improvement of the metabolic stability for -, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of suggested that the -methyl group of the adamantyl moiety is a major site of metabolism.
在本研究中，我们报告了一系列苯并[]噻唑 - 2(3)酮作为σ受体（σRs）配体的构效关系、结合特性和代谢稳定性研究。具体而言，为了提高我们先导化合物（）中环胺片段的代谢稳定性，将代谢不稳定的氮杂环庚烷环替换为1 - 金刚烷胺部分。在合成的类似物中，化合物对σR具有低纳摩尔亲和力（ = 7.2 nM），并且相对于σR具有适度的选择性（61倍）。代谢稳定性研究表明，尽管在大鼠肝微粒体中观察到广泛的代谢，但 - 的代谢稳定性略有改善。此外，对 的代谢软点鉴定表明，金刚烷基部分的 - 甲基是主要的代谢位点。
