Abe Kenji, Saitoh Toshiaki, Horiguchi Yoshie, Utsunomiya Iku, Taguchi Kyoji
Department of Neuroscience, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo 194-0042, Japan.
Biol Pharm Bull. 2005 Aug;28(8):1355-62. doi: 10.1248/bpb.28.1355.
Parkinson's disease involves the progressive degeneration of dopaminergic neurons in the substantia nigra. However, the etiology of the disease remains to be elucidated. Endogenous amines, such as 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives present in the mammalian brain, are known to participate in the pathogenesis of Parkinson's disease. These endogenous neurotoxins have been extensively studied because of their structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an agent widely used for generating animal models of Parkinson's disease-like symptoms. Investigations of the synthesis and pharmacological properties of TIQ derivatives are expected to contribute to the development of new therapeutic agents for treating Parkinson's disease. In the present study, we describe more efficient synthesis methods for TIQ derivatives via Pummerer-type cyclization of the substrate N-acyl sulfoxide. Furthermore, the modified Pummerer reaction provided a convenient and efficient method for synthesizing various TIQs. TIQ and its derivative, 1-benzyl-TIQ, can induce parkinsonism in primates and rodents. On the other hand, one TIQ derivative, 1-methyl-TIQ, has been shown to prevent MPTP, TIQ, and 1-benzyl-TIQ induced behavioral abnormalities. Therefore, TIQ derivatives are considered to play an important role in both the onset and prevention of Parkinson's disease. In this article, we focus on the synthesis and pharmacological aspects of 1,2,3,4-tetrahydroisoquinoline derivatives in Parkinson's disease.
帕金森病涉及黑质中多巴胺能神经元的进行性退化。然而，该疾病的病因仍有待阐明。已知哺乳动物脑中存在的内源性胺类，如1,2,3,4-四氢异喹啉（TIQ）衍生物，参与帕金森病的发病机制。由于这些内源性神经毒素的结构与1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）相似，MPTP是一种广泛用于产生帕金森病样症状动物模型的试剂，因此对其进行了广泛研究。对TIQ衍生物的合成和药理性质的研究有望为开发治疗帕金森病的新治疗剂做出贡献。在本研究中，我们描述了通过底物N-酰基亚砜的普默勒型环化反应更有效地合成TIQ衍生物的方法。此外，改进的普默勒反应为合成各种TIQ提供了一种方便有效的方法。TIQ及其衍生物1-苄基-TIQ可在灵长类动物和啮齿动物中诱发帕金森综合征。另一方面，一种TIQ衍生物1-甲基-TIQ已被证明可预防MPTP、TIQ和1-苄基-TIQ诱导的行为异常。因此，TIQ衍生物被认为在帕金森病的发病和预防中都起着重要作用。在本文中，我们重点关注帕金森病中1,2,3,4-四氢异喹啉衍生物的合成和药理学方面。
