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Biomedical subjects

S Shuto

Publications and source records attributed to S Shuto.

68 records · Page 4Linked to original sources
PubMed1978

Pharmacological properties of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e] [1,4]diazepine (Y-7131), a new anti-anxiety drug.

6-(o-Chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thienol[2,3-e][1,4]diazepine (Y-7131), a new derivative of the thienodiazepines, had marked activities in antipentylenetetrazole effect in mice, attenuation of conflict behavior in rats, inhibition of aggressive behavior induced by hypothalamic stimulation in cats and muscle relaxant effects in normal and decerebrate cats. Y-7131 had weak activities in anti-MES effect in mice and loss of righting reflex in mice. The acute toxicity of Y-7131 was considerably lower than that of diazepam. No significant autonomic or neuroleptic effects were noted. Y-7131 appears to be a characteristic and potent anti-anxiety agent different from the benzodiazepines.

Aggression↗
PubMed1978

Protective effect of a novel imidazole derivative against cerebral anoxia.

The protective effect of 1-[2-(2-chlorobenzoyl)-4-nitrophenyl]-2-(diethylaminomethyl) imidazole fumarate (Y-9179) against cerebral anoxia was investigated with a variety of experimental models in mice and rats. Y-9179, at doses lower than 1 mg/kg, showed a consistent protective action against the cerebral anoxia in all of the models studied: hypoxia, ischemia, histotoxic and asphyxic anoxia. The antianoxic activity of Y-9179 was found to be about 100 times greater than that of pentobarbital. This anti-anoxic effect was observed at very small doses at which neither sedation nor motor depression was induced. There was no decrease in the protective effect or no adverse effect even at as high a dose as 30 mg/kg, which corresponded to about 150 times the effective dose. The universal anti-anoxic properties of Y-9179 may be useful both clinically and as a pharmacological tool to elucidate the physiological significance of cerebral anoxia.

Animals↗
PubMedDate not supplied

Significance of substrate hydrophobicity for recognition by an oligopeptide transporter (PEPT1).

Our previous paper [(1999) Bioconjugate Chem. 10, 24-31] pointed out that hydrophobicity of substrates/inhibitors plays an important role in the recognition by an oligopeptide transporter (PEPT1) expressed in the human intestinal epithelial cell line Caco-2. To determine the significance of that hydrophobicity, we have now synthesized dipeptide analogues conjugating the epsilon-amino group of Lys in Val-Lys with aliphatic carboxylic acids: acetic acid (C2), propanoic acid (C3), pentanoic acid (C5), hexanoic acid (C6), and decanoic acid (C10). The affinities of these conjugates were estimated by their inhibition of the accumulation rate of Gly-Sar, a well-established substrate for PEPT1. With the increase in length of the hydrocarbon chain of the conjugates, i.e., in the hydrophobicity of the conjugates, the inhibition strengthened. Dixon-Webb plot analysis of the inhibition by the C10-conjugated dipeptide showed competitive inhibition. The trans-stimulation effect of Val-Lys conjugated to C10 or C5 on the uptake of Ceftibuten was observed using rat brush border membrane vesicles. This findings showed that these conjugates are transportable substrates. These results confirmed that the hydrophobicity of substrates/inhibitor is one of the factors in the recognition by PEPT1.

Animals↗
PubMedDate not supplied

Conjugation of dipeptide to fluorescent dyes enhances its affinity for a dipeptide transporter (PEPT1) in human intestinal Caco-2 cells.

Dipeptide transporters in small intestine have a very wide substrate specificity, so that the transporter sometimes serves as a carrier for peptide-like compounds. We have synthesized dipeptide analogues conjugated at an epsilon-amino group of Lys in Val-Lys or Lys-Sar with fluorescent compounds such as fluorescein isothiocyanate and coumarin-3-carboxylic acid. Uptakes of these peptide analogues were examined by measuring intracellular accumulations into monolayers of the human intestinal epithelial cell line Caco-2 expressing the dipeptide transporter PEPT1. Kinetic analysis and effects of addition either of uncoupler (protonophore) or by Gly-Sar, one of the good substrates of PEPT1, revealed that fluorescent dipeptides were taken up by passive diffusion. In contrast, these analogues remarkably inhibited the Gly-Sar uptake by Caco-2 cells. Among the fluorescent analogues synthesized in this paper, Val-Lys(Flu) was the most potent competitive inhibitor against the Gly-Sar uptake with an inhibition constant of 5 microM. This value is the smallest among those ever reported: Val-Lys(Flu) has the highest affinity for PEPT1 among chemicals ever reported. The importance of the hydrophobic part of the substrate was pointed out.

Biological Transport↗
PubMedDate not supplied

Stereospecificity of 6'-C-neplanocin A analogues as inhibitors of S-adenosylhomocysteine hydrolase activity and human immunodeficiency virus replication.

The R- and S-isomers of 6'-C-neplanocin A analogues, which are all known as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their inhibitory effects on Human Immunodeficiency Virus type 1 (HIV-1) replication and HIV-1 Tat-mediated transactivation. The R-isomers showed much greater activity against AdoHcy hydrolase than the S-isomers. The same differential activity was observed against the HIV-1 replication and the Tat transactivation.

Adenosine↗
PubMedDate not supplied

Nucleosides and nucleotides. 192. Toward the total synthesis of cyclic ADP-carbocyclic-ribose. Formation of the intramolecular pyrophosphate linkage by a conformation-restriction strategy in a syn-form using a halogen substitution at the 8-position of the adenine ring.

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N6-trichloroacetyl-2',3'-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5'-5"-diol derivatives 18. When 18 was treated with POCl3 in PO(OEt)3, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5',5"-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.

Adenine↗
PubMedDate not supplied

Intracellular Ca(2+)-mobilizing adenine nucleotides. Synthesis and biological activity of cyclic ADP-carbocyclic-ribose and C-glycosidic analog of adenophostin A.

We designed novel Ca(2+)-mobilizing purine nucleotides, cyclic ADP-carbocyclicribose 4, and its inosine congener 5, and C-glycosidic adenophostin A 6. In the synthesis of cADPR analogs, the intramolecular condensation to form the pyrophosphate linkage should be the key step. We developed an efficient method for forming such an intramolecular pyrophosphate linkage by the activation of the phenylthiophosphate group with I2 or AgNO3. Using this method, we achieved to synthesize the target compounds 4 and 5. The synthesis of C-glycosidic analog 6 of adenophostin A was achieved using a temporary silicon-tethered radical coupling reaction for constructing (3'alpha, 1" alpha)-C-glycosidic structure as the key step.

Adenine Nucleotides↗
PubMedDate not supplied

Synthesis and biological activities of cyclic ADP-carbocyclic-ribose and its analogs.

An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N1-carbocyclic-ribosyladenosine bisphosphate derivative 10 with AgNO3 in the presence of molecular sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was deprotected to give the target cyclic ADP-carbocyclic-ribose (2).

Adenosine Diphosphate Ribose↗