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Synthetic Study of Monoamine Transporter Inhibitor
monoamine neurotransmitter,serotonin,vesicular monoamine transporter type 2,selective serotonin reuptake inhibitor,
|Publication Year :||2018|
|Abstract:||單胺神經遞質為在人體中控制情緒、認知、記憶的重要調控分子。其結構常為一個單胺接上兩個碳之碳鍊再接上芳香環。常見的有多巴胺、血清素、正腎上腺素。調節這些單胺神經遞質的方式最常見的是以單胺轉運蛋白來作調控。在神經中常見的單胺轉運單白分別有多巴胺轉運蛋白(DAT)、血清素轉運蛋白(SERT)、正腎上腺素轉運蛋白(NET)、囊泡單胺轉運蛋白二型(VMAT2)。前三者之作用為將單胺神經遞質從突觸空間轉運至突觸前神經元，後者則將單胺神經遞質從細胞質轉運至突觸囊泡中。這對於單胺神經遞質有非常重要的調節作用。VMAT2已被證明可導致許多臨床神經系統疾病，包括藥物成癮，情緒障礙和壓力，以及帕金森氏症(Parkinson's Disease，PD)和阿茲海默症(Alzheimer's disease，AD)。但目前只知道帕金森氏症、阿茲海默症與VMAT2有關聯，但其中詳細關連並不清楚。而Tetrabenazine是目前美國FDA唯一允許用於治療亨丁頓舞蹈症的藥物，其對於VMAT2具有極高的親合力，其特定構型的代謝物(+)-DTBZ對於VMAT2之親合力為0.97 nM，如何得到(+)-TBZ即為一重要的課題。利用選擇性血清素回收抑制劑 (SSRI)為抑制血清素轉運蛋白的方法。若在其主結構二苯硫苯胺之胺基對位上具有氯原子，其可以增強SSRI對於SERT的抑制效果與加強其選擇性。但若在二苯硫苯胺之結構上以目前已知之氯化反應方法均不能選擇性的在胺之對位上氯化。本實驗室在以氯化亞錫還原硝基時發現了其副反應為在還原後的胺基對位上接上了氯原子，故嘗試以此為基礎來發展在二苯硫苯胺上胺基對位氯化之方法。本研究成功地以不對稱合成得到了(+)-TBZ並探討其應用，也在多種實驗條件下找出一鍋化還原氯化反應的最佳條件。|
Monoamine neurotransmitters are important regulatory molecules that control emotion, cognition, and memory in human brain. The structure is usually a monoamine with two carbon chains attached to the end of the aromatic ring. Dopamine, serotonin, and norepinephrine are common in humans. The most common way to regulate these monoamine neurotransmitters is by monoamine transporters. The monoamine transporters commonly found in nerves are dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and vesicular monoamine transporter type 2 (VMAT2). The role of the first three is to transport monoamine neurotransmitters from the synaptic space to presynaptic neurons, the last one transport monoamine neurotransmitters from the cytoplasm to synaptic vesicles. This has a very important regulatory effect on monoamine neurotransmitters. VMAT2 has been shown to cause many clinical neurological diseases, including drug addiction, mood disorders and stress, as well as Parkinson's Disease (PD) and Alzheimer's disease (AD). However, only Parkinson's disease and Alzheimer's disease are currently associated with VMAT2, but the detailed relationship is not clear. Tetrabenazine is currently the only drug approved by the US FDA for the treatment of Huntington's disease. It has a very high affinity for VMAT2, and its specific configuration of the metabolite (+)-DTBZ has an affinity for VMAT2 of 0.97 nM. How to get (+)-TBZ is an important issue. A selective serotonin reuptake inhibitor (SSRI) is used as a method of inhibiting serotonin transporters. If it has a chlorine atom on the para position of the main structure of diphenylthioaniline, it can enhance the inhibitory effect of SSRI on SERT and enhance its selectivity. However, if the structure of diphenylthioaniline is chlorinated at the para position of the amine by the currently known chlorination reaction method. In our laboratory, when the nitro group was reduced by stannous chloride, a side reaction was found to be a chlorine atom attached to the amine group after the reduction. Therefore, based on this, an amine-based chlorination method on diphenylthioaniline was developed.
In this study, (+)-TBZ was successfully synthesized by asymmetric synthesis and its application was explored. The optimal conditions for one-pot reduction chlorination were also found under various experimental conditions.
|Appears in Collections:||藥學系|
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