Toshiaki Saitoh

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.

Theoretical study on isomeric stabilities of C2H2Si and its ionization potentials and electron affinities.

The geometric structures and isomeric stabilities of various stationary points in C(2)H(2)Si neutral and its cation and anion are investigated at the coupled-cluster singles, doubles (triples) [CCSD(T)] level of theory. For the geometrical survey, the basis sets used are of the Dunnings correlation consistent basis sets of triple-zeta quality (cc-pVTZ) for the neutral and cation. For the anions, the cc-pVTZ basis sets with diffuse functions (aug-cc-pVTZ) are used. The final energies are calculated by the use of the CCSD(T) level of theory with the aug-cc-pVTZ basis set at their optimized geometries. To lower lying neutrals and cations, the Dunnings correlation consistent basis sets of quadruple-zeta quality (cc-pVQZ) are also applied. Both the global minima of the C(2)H(2)Si neutral and cation, N-1 (C(2v):(1)A(1)) and C-1 (C(2v):(2)B(2)), respectively, are silacyclopropenylidene conformers, having a CCSi ring with a C[Double Bond]C double bond. No competitive stable isomers exist in the present C(2)H(2)Si neutral. In the cation, however, the second lowest lying isomer C-2 lies 10.8 kJ/mol above the most stable C-1. The vertical and adiabatic ionization potentials from the lowest lying neutral N-1 are 9.83 and 8.97 eV, respectively, at the CCSD(T)/cc-pVQZ level of theory. The electron addition to the N-1 does not result in the anion with positive (real) electron affinities. On the other hand, the electron addition to the N-2 isomer produces the global minimum anion A-1 (C(2v):(2)B(1)) with the positive electron affinities of 1.13 eV. The second lowest lying anion isomer A-2 with silylenylacetylene conformer, produced from an electron addition to the N-3 neutral, very well competes with the A-1 after the zero-point vibrational energy corrections. The energy difference between the two lowest lying isomers of the neutral and its anion, N-1 and A-1, is only 0.39 eV.

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.

Synthesis of chiral 3-methyl- and 3-methyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline and prevention of MPP+ -induced cytotoxicity.

The chemical structure of selegiline, a commercially available drug for Parkinsons disease (PD), resembles that of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endogenous parkinsonism-inducing compound. In the present study, we evaluated the direct cytotoxicity of (R)- and (S)-3-methyl-TIQ (3-MeTIQ) and (R)- and (S)-3-methyl-N-propargyl-TIQ (3-Me-N-propargyl-TIQ), as selegiline-mimetic TIQ derivatives, and their ability to prevent 1-methyl-4-phenylpyridinium iodide (MPP(+))-induced cell death. Synthesis of optically-pure 3-MeTIQs was achieved via the super acid-induced cyclization of chiral N-benzyl-N-[1-methyl-2-(phenylsulfinyl)ethyl]formamide using a Pummerer-type cyclization reaction as the key step in producing excellent yields. Subsequent N-propargylation of chiral 3-MeTIQs using propynylbromide gave the corresponding 3-Me-N-propargyl-TIQs. In our in vitro experiments, the direct cytotoxicity of chiral 3-MeTIQs and 3-Me-N-propargyl-TIQs was almost identical, with no relationship to optical chirality except for (S)-3-Me-N-propargyl-TIQ, which had significantly weaker direct cytotoxicity than the other 3-MeTIQ derivatives. However, the decreased viability of PC12 cells induced by treatment with MPP(+) was accelerated by the coexistence of 3-MeTIQs and inhibited by 3-Me-N-propargyl-TIQs without any participation of the stereochemistry at the 3-position. These results suggest that the N-propargyl group is necessary for protection of cells against the toxicity of MPP(+). Furthermore, the stereochemistry of the 3-position appears to partially participate in the direct cytotoxicity of 3-Me-N-propargyl-TIQs.

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

An efficient and convenient synthesis of 4,5,6,7-tetrahydrothieno〔3,2-c〕pyridines by a modified Pictet-Spengler reaction via a formyliminium ion intermediate

A synthesis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5) was achieved in a highly efficient manner via trifluoroacetic acid catalyzed cyclization of formyliminium ion (4), which was produced by imination of 2-(2-thienyl)ethylamine (1) and a carbonyl compound (2) using titanium(IV) tetraisopropoxide followed by formylation with acetic-formic anhydride in a one-pot procedure. This modified Pictet-Spengler reaction provides a convenient method for preparing 4,5,6,7-tetahydrothieno[3,2-c]pyridines (6) possessing various substituents at C-4.

Facile synthesis of 1-aryl-2,3-dihydro-1H-isoindoles by cyclization of N-formyliminium ion via geometrically disfavored 5-endo-trig process

Synthesis of 1-aryl-2,3-dihydro-1H-isoindoles (isoindolines) (10) was achieved in a highly effective manner via acid catalyzed cyclization of N-formyliminium ion (8) obtained from 2,3-dimethoxybenzylamine and carbonyl compounds with acetic-formic anhydride under a one pot procedure. This Pictet-Spengler type reaction provides a convenient method for preparing 1-arylisoindolines.