Takehiro Sano

Biochemical and pathological study of endogenous 1-benzyl-1,2,3,4-tetrahydroisoquinoline-induced parkinsonism in the mouse.

We administered 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ; 80 mg/kg, i.p.), an endogenous neurotoxin known to cause bradykinesia, the Parkinsons disease-like symptom, in order to obtain biochemical and pathological evidence of behavioral abnormalities. Immunohistochemical analysis demonstrated that 1-BnTIQ did not decrease the number of tyrosine hydroxylase-positive cells in the substantia nigra. Biochemical analysis demonstrated significantly increased striatal dopamine (DA) content, while DA metabolites in the striatum remained at control levels. We concluded that the 1-BnTIQ-induced bradykinesia has a different mechanism of action than that underlying the MPTP-induced depletion of striatal DA neurons.

Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson’s disease

We carried out behavioral, pathological, and biochemical studies in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) affects the onset of Parkinsons disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. Pretreatment with (R)-1-MeTIQ or its racemate (RS)-1-MeTIQ prevented the TIQ-induced bradykinesia. Pretreatment with a combination of L-DOPA and carbidopa significantly prevented subsequent TIQ-induced bradykinesia. Furthermore, the pathological study demonstrated that either (R)-1-MeTIQ or its racemate protected against TIQ-induced loss of tyrosine hydroxylase-positive cells of the substantia nigra pars compacta. (R)-1-MeTIQ and its racemate also prevented the TIQ-induced reduction in the levels of dopamine and its metabolites in the striatum. Serotonin and its metabolite were not affected by repeated administration of (RS)-1-MeTIQ or its derivatives. On the other hand, (S)-1-MeTIQ induced moderate but significant bradykinesia, whereas (R)-1-MeTIQ did not induce this behavioral abnormality at all. In addition, (S)-enantiomer prevented the onset of TIQ-induced bradykinesia, though to a lesser extent than did either (R)-enantiomer or its racemate. However, (S)-enantiomer did not prevent the loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. We concluded that (R)-1-MeTIQ, and not (S)-enantiomer, plays a crucial role in protection against TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of Parkinsons disease.

Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism‐preventing effect of 1‐MeTIQ by in vivo measurement of pre‐synaptic dopamine transporters and post‐synaptic dopamine D2 receptors in the mouse striatum

Parkinsonism‐inducing neurotoxicity of 1,2,3,4‐tetrahydroisoquinoline (TIQ), as contrasted to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), and parkinsonism‐preventing effect of 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1‐MeTIQ) have been investigated in mice by measuring their effects on the in vivo binding of radioligand to pre‐synaptic dopamine transporters (DATs) or to dopamine D2 receptors (D2R) in the striatum. A significant reduction of the ligand‐DATs binding was found in the mice treated with MPTP, but not with TIQ, under the dosage inducing behavioral abnormality and loss of tyrosine hydroxylase‐positive cells in the substantia nigra. A slight decrease in the ligand‐DATs binding was observed in the mice given a larger dose of TIQ. Compensatory up‐regulation in the post‐synaptic D2Rs was found in the MPTP‐treated mice. Pre‐treatment with (S)‐enantiomer, but not (R)‐enantiomer, of 1‐MeTIQ prevented the degeneration of DATs to some extent. We concluded that the TIQ‐induced parkinsonism model is different from the MPTP‐induced model as evaluated by the radioligand‐DATs binding and that (S)‐1‐MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent.

A Facile Synthesis of 1,1-Disubstituted 1,2,3,4-Tetrahydro-b-carbolines via Trifluoroacetic Acid Catalyzed Pictet- Spengler Reaction Using Titanium(IV) Isopropoxide as an Imination Reagent

A synthesis of 1,1-disubstitued 1,2,3,4-tetrahydro-β-carbolines (13) was achieved in a highly effective manner via the trifluoroacetic acid catalyzed Pictet-Spengler reaction of the keto imines (9) prepared from tryptamine (8) with acyclic and cyclic ketones using titanium(IV) isopropoxide as the imination reagent under one pot procedure. This reaction provides a convenient and general method for preparing various 1,2,3,4-tetrahydro-β-carbolines derivatives.

Stephaoxocanidine, a New Isoquinoline Alkaloid from Stephania cepharantha

Abstract Stephaoxocanidine (2), an isoquinoline alkaloid, was isolated from the tubers of Stephania cepharantha Hayata (Menispermaceae) cultivated in Japan. On the basis of spectroscopic evidence, the structure of 2 was established as 12S-6,7-dimethoxy-12-hydroxystephaoxocane. The absolute configuration was deduced by the modified Moshers method.

No reduction of dopamine transporter binding sites in mice following treatment with the TIQ analogue 1-benzyl-1,2,3,4-tetrahydroisoquinoline

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ) and TIQ are endogenous substances inducing bradykinesia, one of the symptoms of parkinsonism, in rodents and primates, and 2-methyl-TIQ is postulated to be an active form of TIQ. We investigated the effect of 1-BnTIQ-, TIQ- or 2-methyl-TIQ-treatment on the binding of 2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-[N-methyl-11C]tropane to striatal dopamine transporters (DATs) in mice. Neither 1-BnTIQ (80 mg/kg, i.p., twice per day for 10 days) nor 2-methyl-TIQ (40 mg/kg, i.p., twice per day for 10 days) affected the radioligand-DAT binding, while TIQ (80 mg/kg, i.p., twice per day for 10 days) induced a 14% decrease. These results indicate that 1-BnTIQ does not affect the density of DATs on dopaminergic neurons, and that it is not clear whether or not 2-methyl-TIQ is an active form of TIQ.

Synthesis of 1,2-Dihydrobenz[c]azepin-3-one via Acid-catalyzed Cyclization of N-Arylmethyl-N-methyl-3-phenylsulfanylacrylamide

Treatment of N-arylmethyl-N-methyl-cis-3-phenylsulfanyl acrylamide (5) with p-toluenesulfonic acid induced two reactions; cyclization to 1,2-dihydrobenz[c]azepin-3-ones (7) and N-dearylmethylation to N-methylacrylamides (9 and 10) depending on the structures of the substrates. The route provides a simple method of preparing 6-methoxy- (7e), 8-methoxy- (7d), 6,8-dimethoxy- (7f), and 8,9-dimethoxy-N-methyl-1,2-dihydrobenz-[c]azepin-3-ones (7g), although the scope is limited by some side reactions.

Revised assignment of olefinic proton signals in the 1H-NMR spectra of dienoid-type erythrinan alkaloids

Previous assignment of the olefinic proton signals (H-1 and H-2) in the 1 H-nmr spectra of dienoid-type erythrinan alkaloids was interchanged on the basis of the synthesis of the stereoisomers, nOe experiments, and theoretical calculations

Oxidation of dioxopyrroline with m-chloroperbenzoic acid: Selective formation of 2,3-dioxo-1,4-oxazine

Treatment of 4-ethoxycarbonyl-5-phenyl-1H-pyrrole-2,3-diones (1a-1e) and 4-benzoyl-1,5-diphenyl-1H-pyrrole-2,3-dione (1f) with m-chloroperbenzoic acid caused Baeyer-Villiger oxidation to give 2,3-dioxo-1,4-oxazines (2a-2f) in moderate yields, respectively. This conversion of the 1H-pyrrole-2,3-dione into the 2,3-dioxo-1,4-oxazine provides the first synthesis of monocyclic 2,3-dioxo-1,4-oxazine ring system

Thermal cycloaddition of aroylketene to 1-aryl-1-trimethylsilyloxyethylene: a simple synthesis of 2,6-diaryl-4H-pyran-4-one

Aroylketene (2) generated by pyrolytic decarbonylation of 5-aryl-2,3-dihydro-2,3-furandione (1) reacted with 1-aryl-1-trimethylsilyloxyethylene (3) in a regioselective manner to give 2,6-diaryl-4H-pyran-4-one (5) and/or 1,5-diarylpentane-1,3,5-trione (6). This reaction provides a simple synthetic method of 2,6-diaryl-4H-pyran-4-one with various substituents in the aryl group