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

Abstract

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 Pummerertype 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.

A Guide to Neurotoxic Animal Models of Parkinson's Disease

“…Additionally, the effects of 1,2,3,4-tetrahydroisoquinoline in monkeys are not reproduced by other isoquinoline derivatives that have similar properties to 1,2,3,4-tetrahydroisoquinoline (Yoshida et al 1993). Furthermore, some tetrahydroisoquinoline derivatives such as 1-methyl-1,2,3,4-tetrahydroisoquinoline even have neuroprotective effects Abe et al 2005;Okuda et al 2006). Because one isoquinoline derivative can be transformed to another one, for example, 1,2,3,4-tetrahydroisoquinoline (neurotoxic) can be converted by N-methyltransferase in vivo to 1-methyl-1,2,3,4-tetrahydroisoquinoline (neuroprotective), which is then further oxidized by monoamine oxidase to N-methyl-isoquinolinium ion (neurotoxic) (Nagatsu 1997), the overall neurotoxic properties of a particular isoquinoline isoform can be difficult to interpret or predict.…”

1-Methyl-1,2,3,4-tetrahydroisoquinoline Antagonizes a Rise in Brain Dopamine Metabolism, Glutamate Release in Frontal Cortex and Locomotor Hyperactivity Produced by MK-801 but not the Disruptions of Prepulse Inhibition, and Impairment of Working Memory in Rat

“…It was originally believed that tetrahydroisoquinolines, structurally resembling 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP), were neurotoxic, but it was later discovered that some of them were neuroprotective. The action of various compounds of this group ranges from neurotoxicity to neuroprotection, as exemplified by the neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) and the neuroprotectant, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) (Abe et al 2005;McNaught et al 1994;Nagatsu 1997). We demonstrated previously, that various TIQs differ in their effects on dopamine catabolic pathways: monoamine oxidase (MAO)-dependent and catechol-O-methyltransferase (COMT)-dependent pathway.…”

YS 49, 1-(α-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, regulates angiotensin II-stimulated ROS production, JNK phosphorylation and vascular smooth muscle cell proliferation via the induction of heme oxygenase-1

“…Various derivatives of 1,2,3,4-tetrahydroisoquinoline are present in the mammalian brain, being either synthesized there from biogenic amines or acquired through diet (Abe et al, 2005). Tetrahydroisoquinoline and its derivatives are structurally similar to 1-methyl-4-phehyl-1,2,3,6-tetrhydropyridine (MPTP) and may give rise to quaternary ions, and have thus been regarded to be neurotoxic substances (Nagatsu, 1997;McNaught et al, 1998).…”