Biol. Pharm. Bull. 29(7) 1401—1403 (2006)

characterized by degeneration of nigro-striatal dopaminergic neurons and reduction in the level of dopamine in this area. Since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could induce parkinsonism in humans, 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been considered as candidate endogenous causative factors of idiopathic Parkinson’s disease (PD), because of their structural similarity to MPTP. We have reported that tetrahydroisoquinoline derivatives (Fig. 1), such as TIQ, 1-methyl-1,2,3,4tetrahydroisoquinoline (1MeTIQ), 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), and 1-(3 ,4 -dihydroxybenzyl)1,2,3,4-tetrahydroisoquinoline (3 ,4 DHBnTIQ), exist in the brain of mammalians of several species. While the content of 1BnTIQ tends to be increased in cerebrospinal fluid (CSF) of PD patients, 1MeTIQ is significantly decreased in the parkinsonian brain and MPTP-injected mouse brain. Bradykinesia, one of the symptoms of PD, was induced by injection of TIQ, 1BnTIQ, or 3 ,4 DHBnTIQ in mice, so these TIQ derivatives are considered to be parkinsonism-inducing substances. MPTP and TIQ derivatives have inhibitory activities towards complex I of the mitochondrial respiratory chain and tyrosine hydroxylase. MPTPor TIQ-induced bradykinesia was prevented by pretreatment with 1MeTIQ, which also suppressed the inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP ), an active metabolite of MPTP. Thus, 1MeTIQ is a possible endogenous PD-preventing substance. Since 1MeTIQ is an endogenous amine, it may be synthesized enzymatically. Indeed, a candidate enzyme was partially purified from mitochondrial-synaptosomal fraction of rat brain, and its regional distribution was examined in monkey brain. However, the mechanism of the parkinsonism-preventing activity of 1MeTIQ is still unknown. We have synthesized derivatives of 1MeTIQ (Fig. 1) and evaluated their in vitro neurotoxicity and protective activity against toxicity due to salsolinol in SH-SY5Y human neuroblastoma cells. The introduction of one methoxyl group into 1MeTIQ increased the toxicity, especially in the case of 7-methoxy-1MeTIQ. The introduction of one hydroxyl group, however, reduced the toxicity. 1MeTIQ showed a week (not statistically significant) in vitro protective effect against the toxicity of salsolinol. 6or 7-Hydroxy-1MeTIQ showed a greater (statistically significant) protective effect at 20 mM concentration against the toxicity of 20 or 40 mM salsolinol. In the present study, we examined whether these hydroxylsubstituted 1MeTIQ derivatives have parkinsonism-preventing activity in C57BL/6N mice by means of the pole test, and measured the brain dopamine content.