Yoshikazu Tasaki

1‐Methyl‐ 1,2,3,4‐Tetrahydroisoquinoline, Decreasing in 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Treated Mouse, Prevents Parkinsonism‐Like Behavior Abnormalities

In l‐methyl‐4‐phenyl‐l,2,3,6‐tetrahydropyridine (MPTP)‐treated mouse brain, there was no significant increase or decrease in the content of an endogenous amine, 1,2,3,4‐tctrahydroisoquinoline (TIQ), which is well noted for inducing parkinsonism, whereas another endogenous amine, 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1‐MeTIQ), was markedly reduced. This result agrees with the finding in human idiopathic parkinsonianism, confirmed by our previous research. In addition, pretreatment with 1‐MeTIQ completely prevented MPTP‐ or TIQ‐inducing bradykinesia, a symptom of parldnsonism. This study confirmed that 1‐MeTIQ plays an important role in preventing the pathogenesis of parldnsonism and is a possible leading compound of anti‐parkinsonism agents.

Low Levels of mRNA for Dopamine D4 Receptor in Human Cerebral Cortex and Striatum

Abstract: Significant densities of mRNA for the dopamine D4 receptor in cerebral cortex, particularly in frontal lobe, have been reported in rats and monkeys, supporting the D4 hypothesis in the pathology of schizophrenia. Using northern blot analysis and the competitive reverse transcription‐polymerase chain reaction (RT‐PCR) method, we determined the relative levels of D4 mRNA in human brain regions to clarify whether the cortical level is also higher in humans. Northern blot analysis revealed an unexpected profile of D4 mRNA in the brain. The detected mRNA size, 1.5 kb, was quite different from the 5.3 kb reported in human neuroblastoma SK‐N‐MC cells. Higher levels of D4 mRNA were detected not only in the mesolimbic system but also in the corpus callosum, spinal cord, medulla, and subthalamic nucleus. It was surprising that in the cerebral cortex regions as well as the striatum, D4 mRNA was hardly detected. The competitive RT‐PCR revealed these relative densities to be at least three orders of magnitude lower than that of the striatal D2 receptor. Our results demonstrate a remarkable difference in cortical D4 mRNA density in humans compared with that in rats and monkeys. Furthermore, the mRNA distribution suggests that the higher density of D4‐like binding sites reported recently in normal human striatum is not due to the D4 receptor.

Chronic administration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine in the brain, induces parkinsonism in a primate ☆

1-Benzyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1Bn TIQHCl) (22 mg/kg per day) was subcutaneously injected into a monkey, Macaca fascicularis for 66 days to investigate its acute and chronic effects Parkinsonism like motor symptoms appeared, and the acute toxicity was stronger than the chronic toxicity. This result suggested that 1BnTIQ may induce parkinsonism in humans. 1BnTIQ content in various regions of the monkey brain was determine by the gas chromatography-selected ion-monitoring method, but no significant variation was found.

Metabolism and brain accumulation of tetrahydroisoquinoline (TIQ) a possible parkinsonism inducing substance, in an animal model of a poor debrisoquine metabolizer

4-Hydroxytetrahydroisoquinoline (4OH-TIQ) was detected as a metabolite of a possible parkinsonism-inducing substance, tetrahydroisoquinoline (TIQ), in rat liver microsomes and rat urine. Urinary excretion of 4OH-TIQ was significantly reduced in female DA rat, an animal model of a poor debrisoquine metabolizer. The female DA rat also showed significantly higher brain accumulation of TIQ. These results suggest that the metabolic detoxication process is depressed and TIQ accumulation in the brain is enhanced in a poor debrisoquine metabolizer, which may be one possible explanation for poor debrisoquine metabolizers being susceptible to Parkinsons disease.

Neuroprotective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on cultured rat mesencephalic neurons in the presence or absence of various neurotoxins

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous brain amine and its content in parkinsonian brain is decreased compared with that in control brain. There is some evidence that 1MeTIQ protects dopaminergic neurons against dysfunction such as that seen in Parkinsons disease. In this study, we examined the neuroprotective effect of 1MeTIQ against four dopaminergic neurotoxins, 1-methyl-4-phenylpyridinuim ion, 6-hydroxydopamine, rotenone, and l-benzyl-1,2,3,4-tetrahydroisoquinoline, in cultured rat mesencephalic neurons. 1MeTIQ exerted neuroprotective action against all these toxins. Furthermore, (R)-1MeTIQ was neuroprotective, while (S)-1MeTIQ had little effect, indicating that the effect is stereoselective. The protective action of 1MeTIQ was most effective in mesencephalic neurons, especially in tyrosine hydroxylase-positive neurons. 1MeTIQ showed no affinity for dopamine receptors and did not influence the inhibition of mitochondrial respiratory complex I by rotenone, 1-methyl-4-phenylpyridinuim ion, or 1-benzyl-1,2,3,4-tetrahydroisoquinoline. These results raise the possibility that 1MeTIQ indirectly acts as an anti-oxidant such as the induction of anti-oxidative enzymes, because all these four neurotoxins can burden oxidative stress in common. This is the first report to confirm a protective effect of 1MeTIQ at the cultured neuron level, and it may have potential as a lead compound for the development of new agents to treat Parkinsons disease.

Deprenyl decreases an endogenous parkinsonism-inducing compound, 1-benzyl-1,2,3,4-tetrahydroisoquinoline in mice: in vivo and in vitro studies.

We examined the effect of deprenyl, a promising drug for the therapy of Parkinsons disease on the formation of a parkinsonism-inducing compound, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ). The 1BnTIQ content was significantly decreased in the brain of deprenyl-treated mouse in vivo, and deprenyl also inhibited 1BnTIQ formation from phenethylamine by a mouse brain homogenate supernatant in vitro. In vivo, the content of a parkinsonism-preventing compound, 1-methyl-1,2,3, 4-tetrahydroisoquinoline (1MeTIQ) was slightly increased in mice injected with deprenyl. The marked decrease of the ratio of 1BnTIQ to 1MeTIQ might play a role in the clinical effect of deprenyl.

A Novel and Neurotoxic Tetrahydroisoquinoline Derivative In Vivo: Formation of 1,3-Dimethyl-1,2,3,4-Tetrahydroisoquinoline, a Condensation Product of Amphetamines, in Brains of Rats Under Chronic Ethanol Treatment

Abstract: Repeated amphetamine administration to rats under chronic ethanol intoxication resulted in the formation of 1,3‐dimethyl‐1,2,3,4‐tetrahydroisoquinoline (1,3‐DiMeTIQ), a novel metabolite of amphetamines. 1,3‐DiMeTIQ was quantified with a sensitive, specific assay using gas chromatography‐mass spectrometry. It was not found in the brains of rats given repeated amphetamine administration but no ethanol. The chronic ethanol‐intoxicated rats subjected to repeated amphetamine administration exhibited behavioral abnormalities, such as repeated convulsions and curving of the back. 1,3‐DiMeTIQ contents were markedly higher in the brain or plasma of rats manifesting abnormal behavior in comparison with those in rats behaving normally. Thus, the 1,3‐DiMeTIQ content in the rat brain seems to have some relationship with behavioral abnormalities. This study also confirmed that 1,3‐DiMeTIQ can cross the blood‐brain barrier in the rat. Intraperitoneal 1,3‐DiMeTIQ injections to rats caused behavioral symptoms similar to those observed in rats with chronic ethanol intoxication and repeated amphetamine administration. The effect of toxic doses of 1,3‐DiMeTIQ on dopaminergic and serotonergic metabolism in the whole rat brain was also investigated.

In vitro pharmacological profile of YM‐43611, a novel D2‐like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors

1 We investigated some neurochemical properties of a novel benzamide, YM‐43611, [(S)‐S‐(1‐benzyl‐3‐pyrrolidinyl)‐5‐chloro‐4‐cyclopropylcarbonyl‐2‐methoxybenzamide] in comparison with putative D2‐like receptor antagonists using both rat and human cloned dopamine D2‐like receptors in vitro. 2 Receptor binding studies revealed that YM‐43611 had appropriately potent affinities for both rat and human D2‐like receptors, with moderate selectivity for D3 receptors and high selectivity for D4 receptors over D2 receptors (Ktvalues (nM) for rat receptors: D2, 165; D3, 35.5; D4, 1.85, and for human receptors: D2 42.9; D3, 11.2; D4, 2.10). 3 YM‐43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D1, D5, α1, α2, β, 5‐HT1A, 5‐HT2A, 5‐HT3, H1, M1 and M2 receptors. 4 Dopamine stimulated low‐Km GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D2‐like receptor subtype. This response to dopamine of low‐Km GTPase activity was inhibited by use of putative D2‐like receptor antagonists. YM‐43611 showed a moderate selectivity for D3 receptors (Ki=45.5 nM) and a high selectivity for D4 receptors (Ki=3.28 nM) over D2 receptors (Ki=70.6 nM). 5 Dopamine inhibited forskolin‐stimulated adenylate cyclase in intact CHO cells expressing the human D2‐like receptor subtype. YM‐43611 shifted the inhibition curve of dopamine on respective D2‐like receptor subtype‐mediated cyclic AMP formation to the right in a parallel fashion, showing a pA2 value of 7.42 (38.1 nM) for D2 receptors, a pKB> value of 8.06 (8.68 nM) for D3 receptors, and a pA2 value of 8.42 (3.77 nM) for D4 receptors. 6 YM‐43611 but not the other D2‐like receptor antagonists exhibited good selectivity with respect to dual antagonism for D3 and D4 receptors in both receptor binding and functional assays. 7 These results indicate that YM‐43611 is a novel D2‐like receptor antagonist with high potency and selectivity for both D3 and D4 receptors. YM‐43611 is therefore expected to be valuable in exploration of the physiological role of D3 and D4 receptors.

Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors

We compared some binding parameters of [3H]nemonapride and [3H]spiperone in human dopamine D4 (hD4) receptors with three different numbers of tandem repeat units. Although both of the radioligands showed similar affinity constants for each hD4 receptor variant, the maximal number of binding sites labeled by [3H]nemonapride was approximately 1.35-fold higher than that by [3H]-spiperone for all variants. Estimated Ki values for the inhibition of [3H]nemonapride binding by a series of dopaminergic ligands were highly correlated to respective values obtained for the inhibition of [3H]spiperone binding to each hD4 receptor. These results suggest that the hD4 receptor, as shown for the D2 receptor, may exist in multiple molecular forms as a monomer-dimer equilibria, and that [3H]spiperone may discriminate in the multiple molecular forms.

Formation of a Novel and Neurotoxic Tetrahydroisoquinoline Derivative, 1,3-Dimethyltetrahydroisoquinoline (1, 3DiMeTIQ), a Condensation Product of Amphetamines and Acetaldehyde in Vivo

d-Amphetamine and alcohol are generally thought to be mutually antagonistic with respect to their pharmacological action. However the toxic effect of d-amphetamines is not appreciably reduced by the concomitant administration of alcohol.1 It is reported that the combined abuse of methamphetamine and alcohol causes a significant increase in psychosomatic disorders than the abuse of methamphetamine only.2 We hypothesized that a novel metabolite of amphetamines may be involved in such disorders and proposed that 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are formed by ring cyclization of endogenous phenylethylamine.3–5 In the present study, we examined the possibility that 1,3DiMeTIQ could be formed from exogenous amphetamines, an analog of phenylethylamine, by cyclization with acetaldehyde, a metabolite of ethanol (Fig. 1).