Biomedical subjects

Kenji Tomita

Publications and source records attributed to Kenji Tomita.

8 recordsLinked to original sources

PubMed2007

Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres.

Fmoc-protected Phe-Gly-type (Z)-alkene dipeptide isostere (ADI) and (E)-fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc-based solid-phase peptide synthesis (SPPS). These cis-peptide bond mimetics were introduced into a bioactive pentapeptide [H-Amb-Phe-Gly-Leu-Arg-Trp-NH(2); Amb = 4-(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)-ADI-containing derivative. This suggests that the trans-amide conformer of Phe-Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)-FADI-containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI-bioisosterism.

Alkenes↗

PubMed2006

A novel one-pot reaction involving organocopper-mediated reduction/transmetalation/asymmetric alkylation, leading to the diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres.

By a novel one-pot reaction sequence involving consecutive organocopper-mediated reduction, transmetalation and asymmetric alkylation, a highly diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres was achieved in good to excellent yields.

Alkenes↗

PubMed2006

Structure-activity relationship study on small peptidic GPR54 agonists.

Metastin (kisspeptin-54) is an endogenous ligand that modulates gonadotropin-releasing hormone (GnRH) secretion through the interaction with a G protein-coupled receptor (GPCR), GPR54. The short-chain C-terminal decapeptide amide, metastin (45-54) (kisspeptin-10), exerts the identical bioactivities to metastin, such as metastasis suppression of cancer cells and inhibition of trophoblast migration and invasion. In order to understand the structural requirement for GPR54 agonistic activity, structure-activity relationship (SAR) study on pentapeptide-based C-terminal metastin analogues was carried out. As a result, H-Amb-Nal(2)-Gly-Leu-Arg-Trp-NH2 34 was identified as a novel GPR54 agonist that possessed the most potent GPR54 agonistic activity reported so far.

Alkylation↗

PubMed2006

Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives.

Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.

Amino Acids↗

PubMed2006

Unequivocal synthesis of (Z)-alkene and (E)-fluoroalkene dipeptide isosteres to probe structural requirements of the peptide transporter PEPT1.

[reaction: see text] Described is a novel synthetic route for dipeptide isosteres containing (Z)-alkene and (E)-fluoroalkene units as cis-amide bond equivalents via organocopper-mediated reduction of gamma-acetoxy- or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-lactams. The synthesized isosteres were evaluated in terms of their affinities for the peptide transporter PEPT1. trans-Amide isosteres tended to possess higher affinities for PEPT1 as compared to the corresponding cis-amide bond equivalents.

Alkenes↗

PubMed2005

Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity.

Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and d-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors.

Amino Acid Motifs↗

PubMed2004

Facile synthesis of membrane-embedded peptides utilizing lipid bilayer-assisted chemical ligation.

Lipid bilayer-assisted chemical ligation between thiolester and N-terminal cysteine peptides has been developed with successful application to the synthesis of membrane protein segments possessing both two transmembrane and one extracellular regions.

Amino Acid Sequence↗

PubMed2004

The inter-rater reliability of the Japanese version of the Montgomery-Asberg depression rating scale (MADRS) using a structured interview guide for MADRS (SIGMA).

The inter-rater reliability of the Japanese version of MADRS (MADRSJ) was examined using the structured interview guide for MADRS (SIGMA) developed by our group. Two or more psychiatrists attended the systematic interview sessions with each subject to evaluate MADRSJ independently, using SIGMA. A total of 18 interviews was carried out for seven patients with DSM-IV major depressive disorder. The severity of each item assessed by the raters ranged from 0 to 6 for nine items and from 0 to 4 for one item. The analysis of variance intraclass correlation coefficient inter-rater reliability values for the individual items carried out by two trained personnel ranged from 0.91 to 1.00, while those achieved by three raters ranged from 0.85 to 1.00. The present results suggest that SIGMA is a potentially useful interview guide for assessing ten symptoms of MADRSJ precisely in patients with a depressive disorder.

Adult↗