| Summary: | 博士 === 國立臺灣大學 === 藥學研究所 === 107 === 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.
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