Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany.
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149 Münster, Germany.
Bioorg Med Chem. 2019 Dec 1;27(23):115146. doi: 10.1016/j.bmc.2019.115146. Epub 2019 Oct 8.
In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc), HCOH, phosphane ligand) or the 6-hydroxyketone 10 (H, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc) afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of K = 49 nM and a cytoprotective activity of IC = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CHOH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
在这项研究中，分析了苯并[7]轮烯支架上一个或两个羟基对 GluN2B 亲和力和细胞保护活性的影响。OH 取代的苯并[7]轮烯胺 11-13 和 17 的关键中间体是环氧酮 8。8 的还原环氧化物开环具有高度区域选择性，生成 5-羟基酮 9（Pd(OAc)、HCOH、膦配体）或 6-羟基酮 10（H、Pd/C），而在水二氧六环中水解得到二羟基酮 14。这些酮与伯胺和 NaBH(OAc)的还原胺化得到苯并[7]轮烯胺 11-13 和 17。在受体结合研究中，5-OH 衍生物 11 和 12 比 6-OH 衍生物 13 表现出更高的 GluN2B 亲和力，而 6-OH 衍生物 13 又比 5,6-二-OH 衍生物 17a 更具活性。配体的细胞保护活性也遵循相同的顺序。在 5 位具有一个 OH 基团的叔胺 12a 是最有前途的 GluN2B 负变构调节剂，其结合亲和力为 K = 49 nM，细胞保护活性为 IC = 580 nM。在结合口袋中，12a 显示出苄基 OH 基团与 GluN1b 的骨架羰基 O-原子之间的关键氢键。结论是，5-OH 基团对于抑制 NMDA 受体相关离子通道是必不可少的，而 6-位的 OH 基团对于结合和抑制是有害的。2-位的 OH 或 CHOH 基团导致结合在ifenprodil 结合位点，但对离子通道的抑制作用非常弱。
