新穎六取代四氫異喹啉血清素受體之合成研究

Abstract

血清素受器被發現和許多疾病有高度相關，如精神類疾病或者神經退化疾病，且血清素及血清素受器的調節在許多中樞神經系統疾病和腸胃道相關疾病都扮演重要角色。然而血清素受器配體在開發過程中常面臨到選擇性及分佈的問題，因此開發新穎骨架以研究血清素亞型之間差異及藥理活性仍保持高度重要性。過往研究多以 7-Hydroxy-8-phenyl-1,2,3,4-tetrahydroisoquinoline 骨架研發新穎血清素受器配體，然而受限於合成問題，目前的血清素受器配體大多為甲氧基取代而缺乏 6 號位官能基取代的多樣性，因此建立一系列的 6 號位取代衍生物具有高度研究價值。本作以此骨架為基礎並延續實驗室先前的研究，成功合成出化合物 30、化合物 34 及化合物 35，分別為 6-碘、6-氰及 6-溴取代衍生物。合成路徑以 4-Hydroxybenzaldehyde 為起始物，先進行 Henry reaction 得到化合物 18，接著經 LiAlH4 還原得到的 amine 再以 Pictet-Spengler 反應環化，硝化後得到關鍵中間體 21。接著利用 Sandmeyer reaction 作為關鍵合成步驟以平行建立多樣六取代的四氫異喹啉衍生物。最後經去保護基及 Suzuki coupling 將四氫異喹啉主結構和芳香基團作連接，再將 tosyl group 去除後得到二級胺以利未來接上合適的側鏈並用於生物活性測試，以探討其作為新穎血清素受器配體之可能性。

Serotonin receptors were found to be highly related to various diseases, such as mental disorders and neurodegeneration, and their regulation had been known to play important roles in several CNS and GI diseases. Yet, selectivity and distribution are both problems in the developmental stage, thus novel skeletons are still in need for the future understanding of 5-HT subtypes distribution and their pharmacological role. In previous studies, 7-hydroxy-8-phenyl-1,2,3,4-tetrahydroisoquinoline was often selected as the core structure to develope novel serotonin receptor ligands. However, due to the difficulty for the synthesis of this series of compounds, most derivatives were constrained to 6-methoxy substitution. Seeking for a better synthetic route that allowed to construct 6-substituted derivatives would lead to a better understanding of SAR. In this study, 7-hydroxy-8-phenyl-1,2,3,4- tetrahydroisoquinoline was selected as the core structure and compound 30, compound 34, and compound 35 were successfully synthesized, which beared 6-iodine, 6-cyanide, and 6-bromine substitutions respectively. Starting material 4-hydroxybenzaldehyde was converted to compound 18 through benzylation and Henry reaction, then 18 was reduced to amine by LiAlH4. After Pictet-Spengler cyclization and nitration, key intermediate compound 21 was synthesized. Parallel synthesis of diverse 6-substituted tetrahydroisoquinoline derivatives were achieved by Sandmeyer reaction which was the key synthetic step. Then, debenzylation, Suzuki coupling, and detosylation yielded secondary amine, which proper linker can be attached to and applied for further investigation of its biological activity and drug-like property in order to assess its potential as novel serotonin receptor ligands.