Synthesis and Neurotoxicity of Tetrahydroisoquinoline Derivatives for Studying Parkinson's Disease

• Published in: Biological & Pharmaceutical Bulletin Vol. 28; no. 8; pp. 1355 - 1362
• Main Authors: Abe, Kenji, Saitoh, Toshiaki, Horiguchi, Yoshie, Utsunomiya, Iku, Taguchi, Kyoji
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.08.2005; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: 1,2,3,4-tetrahydroisoquinoline; 1-benzyl-1,2,3,4-tetrahydroisoquinoline; 1-methyl-1,2,3,4-tetrahydroisoquinoline; Humans; Parkinson Disease - metabolism; Parkinson's disease; Primates; Pummerer type cyclization; Stereoisomerism; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - toxicity
• ISSN: 0918-6158; 1347-5215
• 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.