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.