2001 年度実績報告書

生物新機能と創薬をめざす生体内分子科学

研究課題

研究課題/領域番号	13NP0401
研究種目	創成的基礎研究費
研究機関	岐阜大学
研究代表者	鈴木正昭岐阜大学, 工学部, 教授 (90093046)
研究分担者	袖岡幹子東北大学, 多元物質科学研究所, 教授 (60192142) 松田彰北海道大学, 大学院・薬学研究科, 教授 (90157313) 渡辺恭良大阪市立大学, 大学院・医学研究科, 教授 (40144399) 橋本祐一東京大学, 分子細胞生物学研究所, 教授 (90164798) 長野哲雄東京大学, 大学院・薬学系研究科, 教授 (20111552)
キーワード	サリドマイド / リピドA / 15R-TIC / リアノジン受容体 / PGE_2 / アロディニア / DNAチップ / PET
研究概要	今年度に達成されたの主な具体的成果を箇条書きにした。 (1)分子プローブ設計グループサリドマイドの多様な薬理作用を標的に構造展開を行い、強力なTNF-α産生調節剤、新型アンドロゲンアンタゴニスト、ピューロマイシン感受性アミノペプチダーゼ特異的阻害剤、α-グルコシダーゼ阻害剤などを創製した。アフィニティ分離を活用した迅速合成法を確立し、リピドAのアシル基に多様性を持つ種々の類縁体を設計・合成した。これにより、アシル鎖の重要性を明らかにするとともに、サイトカイン誘導活性を制御する類縁体の創製に成功した。中枢神経系型プロスタサイクリン受容体(IP_2)探索分子15R-TICをもとに、受容体同定のための光親和性標識プローブ、精製のためのアフィニティゲルの合成に成功した。また、骨格筋小胞体からのCa^<2+>放出制御分子の同定を目的に光親和性標識プローグを設計し、リアノジン受容体の生理的Ca^<2+>放出を抑制するプローブGIF-0082の創製に成功した。 (2)分子機能解析グループプロスタグランジンE_2の発熱に関わる経路の同定を行い、視策前野のEP_3受容体を介したPGE_2のシグナルが延髄淡蒼縫線核吻側部を介して交感神経へ伝達され発熱を誘発することを明らかにした。鈴木らが合成した探索分子GIF-0082が生理的Ca^<2+>放出にのみ抑制効果を持つことを明らかにし、光親和性標識実験により特異的結合を示すタンパク質の捕獲に成功した。DNAチップを用いたトランスクリプトーム解析により、低酸素刺激により変化する遺伝子の解析に成功した。また、PPARγリガンドの投与により遺伝子発現に変化が生じることを確認した。 (3)生体機能評価グループアクロメリン酸が種々の薬剤で誘発されるアロディニアを消失されることを見いだし、新規のグルタミン酸受容体と結合している可能性を示した。この受容体同定に向けて合成された化合物が髄腔内投与によりアロディニアを誘発することを確認した。 (4)分子イメージンググループ老齢および老齢のアカゲザルを用いてドーパミン、セロトニン、アセチルコリン等の受容体リガンドのPETトレーサーを活用した比較実験を行い、脳の老化が及ぼす中枢系受容体の変化や薬理作用への影響を解析した。反応剤や製造ルートのクリーン化などによりPETトレーサー合成における高比放射能化を実現し、世界最高水準のベンゾジアゼピン受容体およびドーパミン受容体の合成に成功した。

研究成果

(44件)

すべてその他

すべて文献書誌 (44件)

[文献書誌] T.Satoh: "Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins"J.Neurochem. 77・1. 50-62 (2001)
[文献書誌] S.Fukushima: "Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-Δ^7-prostaglandin A_1 methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826)"Anticancer Drugs. 12・3. 221-234 (2001)
[文献書誌] T.Ikemoto: "Effects of dantrolene and its derivatives on Ca^<2+> from the sarcoplasmic reticulum of mouse skeletal muscle fibres"Br.J.Pharmacol.. 134・4. 729-736 (2001)
[文献書誌] Y.Sasaki: "NOVEL AND SPECIFIC Rho-KINASE INHBITOR, H1152P, DIRECTED AGAINST THE Rho-KINASE INVOLVED PATHWAY"CELL.MOL.BIOL.LETT.. 6・2B. 506 (2001)
[文献書誌] 鈴木正昭: "陽電子放射断層画像撮影法(PET法)によるヒト脳機能分析のための高次プロスタグランジン(PG)プローブの創製"ファルマシア. 37・11. 994-998 (2001)
[文献書誌] T.Takamatsu: "Specific ligand for a central type prostacyclin receptor attenuates damage in a rat model of focal cerebral ischemia"Brain Research. 925・2. 176-182 (2002)
[文献書誌] S.Shuto: "Total synthesis of cyclic ADP-carbocyclic-ribose, a stable mimic of Ca^<2+>-mobilizing second messenger cyclic ADP-ribose"J.Am.Chem.Soc.. 123・36. 8750-8759 (2001)
[文献書誌] T.Usui: "Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase : implications for the molecular mechanism of the inhibition"Chem.& Biol.. 8・12. 1209-1220 (2001)
[文献書誌] M.Sodeoka: "Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and cdc25B inhibition"J.Med.Chem.. 44・20. 3216-3222 (2001)
[文献書誌] M.Sodeoka: "Asymmetric synthesis of a 3-acyltetronic acid derivative, RK-682, and formation of its calcium salt during silica gel column chromatography"Chem.Pharm.Bull.. 49・2. 206-212 (2001)
[文献書誌] S.Motoori: "Overexpression of Mitochondrial Manganese Superoxide Dismutase Protects Againt Radiation-Induced Cell Death in Human Hepatocellular Carcinoma Cell Line, HLE"Cancer Research. 61・14. 5382-5388 (2001)
[文献書誌] M.Wada: "Synthesis and Optical Properties of a New-Class of Pyrromethene-BF_2 complex Fused with Rigid Bicycle Rings and Benzo Derivatives"Tetrahedron Letters. 42・38. 6711-6713 (2001)
[文献書誌] N.Suzuki: "Orthogonality of Calcium Concentration and Ability of 4, 5-Diaminofluorescein (DAF-2) to Detect NO"J.Biol.Chem.. 277・1. 47-49 (2002)
[文献書誌] Ye Hashimoto: "Structural development of biological response modifiers based on thalidomide"Bioorg.Med.Chem.. 10・3. 461-479 (2002)
[文献書誌] S.Sou: "α-Gluctural inhibitors with a 4, 5, 6, 7-tetrachlorophthalimide skeleton pendanted with a cycloalkyl or dicarba-closo-dodecarborane group"Chem.Pharm.Bull.. 49・6. 791-793 (2001)
[文献書誌] T.Kita: "Thymidine phosphorylase inhibitors with a homophthalimide skeleton"Biol.Pharm.Bull.. 24・7. 860-862 (2001)
[文献書誌] H.Kakuta: "Aminopeptidase inhibitors : 3-(2, 6-diethylphenyl)-2,4(1H, 3H)-quinazolinedione and N-(2, 6-diethylphenyl)-2-amini-4H-3, 1-benzoxazin-3-one"Heterocycles. 55. 1433-1438 (2001)
[文献書誌] S.Akashi: "Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition"Int Immunol.. 13・12. 1595-1599 (2001)
[文献書誌] Y.Fukase: "New Efficient Route for Synthesis of Lipid A by using Affinity Separation"Synlett. 11. 1693-1698 (2001)
[文献書誌] Y.Shigeri: "Effects of threo-β-hydroxyaspartate derivatives on excitatory amino acid transporters (EAAT4 and EAAT5)"J.Neurochem. 79・2. 297-302 (2001)
[文献書誌] M.Ebisawa: "Novel retinoidal tropolone derivatives. Bioisosteric relationship of tropolone ring with benzoic acid moiety in retinoid structure"Chem.Pharm.Bull.. 49・4. 501-503 (2001)
[文献書誌] Y.Endo: "Structure-Activity study of retinoid agonists bearing substituted dicarba-closo-dodecaborane. Relation between retinoidal acitivity and conformation of two aromatic nuclei"Bioorg.Med.Chem.Lett.. 11・10. 1307-1311 (2001)
[文献書誌] T.Yamauchi: "Replenishment of the fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7・8. 941-946 (2001)
[文献書誌] T.Yamauchi: "Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108・7. 1001-1013 (2001)
[文献書誌] H.Torigoe: "Promotion of triplex formation by 2'-O, 4'-C-methilene bridged nucleic acid (2', 4'-BNA) modification : thermodynamic and kinetic studies"Nucleosides Nucleotides Nucleic Acids.. 20・4-7. 1235-1238 (2001)
[文献書誌] S.Obika: "2'-O, 4'-C-Methylene bridged nucleic acid (2', 4'-BNA ) : synthesis and tripllex-forming properties"Bioorg.Med.Chem.. 9・4. 1001-1011 (2001)
[文献書誌] S.Obika: "A 2', 4'-Bridged Nucleic Acid Containing 2-Pyridone as a Nucleobase : Efficient Recognition of a C・G Interruption by Triplex Formation with a Pyrimidine Motif"Angew.Chem.Int.Ed.Engi.. 40・11. 2079-2081 (2001)
[文献書誌] 石川智久: "ゲノム創薬に何が必要か?"現代化学. 11月. 56-60 (2001)
[文献書誌] T.Ikemoto: "Properties of Ca^<2+> release induced by clofibiric acid in the sarcoplasmic reticulum of mouse skeletal muscle fibres"Br.J.Pharmacol.. 134・4. 719-728 (2001)
[文献書誌] K.Nakamura: "Prostaglandin EP3 receptor protein in serotonin and catecholamine cell groups : a double immunofluorescence study in the rat brain"Neuroscience. 103・3. 763-775 (2001)
[文献書誌] S.Akiyoshi: "Targets of transcriptional regulation by transforming growth factor-beta : Expression profile analysis using oligonucleotide arrays"Jpn.J.Cancer Res.. 92・3. 257-268 (2001)
[文献書誌] Y.Hippo: "Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes"Cancer Res.. 61・3. 889-895 (2001)
[文献書誌] T.Kamimoto: "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1"J.Biol.Chem.. 276・40. 37520-37528 (2001)
[文献書誌] T.Kojima: "Cloning of Human PRP4 Reveals Interaction with Clk1"J.Biol.Chem.. 276・34. 32247-32256 (2001)
[文献書誌] M.Osada: "Regulatory Domain of Protein Stability of Human P51/TAP63, a P53 Homologue"Biochem.& Biophys.Res.Comm.. 283・5. 1135-1141 (2001)
[文献書誌] S.Aritani: "Dual roles of RNA helicase A in CREB-dependent transcription"Mol.Cell Biol.. 21・14. 4460-4469 (2001)
[文献書誌] H.R.Ueda: "Robust oscillations within the interlocked feedback model of drosophila circadian rhythm"J.Theo.Biol.. 210・4. 401-406 (2001)
[文献書誌] S.Maekawa: "Localization of neuronal growth-associated, microtubule-destabilizing factor SCG1O in brain-derived raft membrane microdomains"J.Biochem.. 129・5. 691-697 (2001)
[文献書誌] M.Chida: "[^<18>F] labeled diacylglycerol analogue as potential agent to trace myocardial phosphoinositide metabolism"Nucl.Med.Biology. 28・7. 815-819 (2001)
[文献書誌] T.Valdes-Gonzalez: "Neuropeptides interact with glycolipid receptors : A surface plasmon resonance study"Peptides. 22・7. 1099-1106 (2001)
[文献書誌] H.Tsukada: "Age differences in muscarinic cholinergic receptor assayed with (+)N-[(11)C]methyl-3-piperidyl benzilate in the brains of consious monkeys"Synapse. 41・3. 248-257 (2001)
[文献書誌] T.Kakiuchi: "Age-related changes in muscarinic cholinergic receptors in the living brain : a PET study using N-[^<11>C]methyl-4-piperidyl benzilate combined with cerebral blood flow measurement in conscious monkeys"Brain Res.. 916・1-2. 22-31 (2001)
[文献書誌] H.Tsukada: "Effects of aging on 5-HT(1A) receptors and their functional response to 5-HT(1a) agonist in the living brain : PET study with [carbonyl-(11)C]WAY-100635 in conscious monkeys"Synapse. 42・4. 242-251 (2001)
[文献書誌] T.Kakiuchi: "Effects of aging on serotonin transporter availability and its response to fluvoxamine in the living brain : PET study with"Synapse. 40・3. 170-179 (2001)

2001 年度 実績報告書

生物新機能と創薬をめざす生体内分子科学

研究代表者

鈴木 正昭 岐阜大学, 工学部, 教授 (90093046)

研究成果

[文献書誌] T.Satoh: "Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins"J.Neurochem. 77・1. 50-62 (2001)

[文献書誌] S.Fukushima: "Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-Δ^7-prostaglandin A_1 methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826)"Anticancer Drugs. 12・3. 221-234 (2001)

[文献書誌] T.Ikemoto: "Effects of dantrolene and its derivatives on Ca^<2+> from the sarcoplasmic reticulum of mouse skeletal muscle fibres"Br.J.Pharmacol.. 134・4. 729-736 (2001)

[文献書誌] Y.Sasaki: "NOVEL AND SPECIFIC Rho-KINASE INHBITOR, H1152P, DIRECTED AGAINST THE Rho-KINASE INVOLVED PATHWAY"CELL.MOL.BIOL.LETT.. 6・2B. 506 (2001)

[文献書誌] 鈴木正昭: "陽電子放射断層画像撮影法(PET法)によるヒト脳機能分析のための高次プロスタグランジン(PG)プローブの創製"ファルマシア. 37・11. 994-998 (2001)

[文献書誌] T.Takamatsu: "Specific ligand for a central type prostacyclin receptor attenuates damage in a rat model of focal cerebral ischemia"Brain Research. 925・2. 176-182 (2002)

[文献書誌] S.Shuto: "Total synthesis of cyclic ADP-carbocyclic-ribose, a stable mimic of Ca^<2+>-mobilizing second messenger cyclic ADP-ribose"J.Am.Chem.Soc.. 123・36. 8750-8759 (2001)

[文献書誌] T.Usui: "Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase : implications for the molecular mechanism of the inhibition"Chem.& Biol.. 8・12. 1209-1220 (2001)

[文献書誌] M.Sodeoka: "Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and cdc25B inhibition"J.Med.Chem.. 44・20. 3216-3222 (2001)

[文献書誌] M.Sodeoka: "Asymmetric synthesis of a 3-acyltetronic acid derivative, RK-682, and formation of its calcium salt during silica gel column chromatography"Chem.Pharm.Bull.. 49・2. 206-212 (2001)

[文献書誌] S.Motoori: "Overexpression of Mitochondrial Manganese Superoxide Dismutase Protects Againt Radiation-Induced Cell Death in Human Hepatocellular Carcinoma Cell Line, HLE"Cancer Research. 61・14. 5382-5388 (2001)

[文献書誌] M.Wada: "Synthesis and Optical Properties of a New-Class of Pyrromethene-BF_2 complex Fused with Rigid Bicycle Rings and Benzo Derivatives"Tetrahedron Letters. 42・38. 6711-6713 (2001)

[文献書誌] N.Suzuki: "Orthogonality of Calcium Concentration and Ability of 4, 5-Diaminofluorescein (DAF-2) to Detect NO"J.Biol.Chem.. 277・1. 47-49 (2002)

[文献書誌] Ye Hashimoto: "Structural development of biological response modifiers based on thalidomide"Bioorg.Med.Chem.. 10・3. 461-479 (2002)

[文献書誌] S.Sou: "α-Gluctural inhibitors with a 4, 5, 6, 7-tetrachlorophthalimide skeleton pendanted with a cycloalkyl or dicarba-closo-dodecarborane group"Chem.Pharm.Bull.. 49・6. 791-793 (2001)

[文献書誌] T.Kita: "Thymidine phosphorylase inhibitors with a homophthalimide skeleton"Biol.Pharm.Bull.. 24・7. 860-862 (2001)

[文献書誌] H.Kakuta: "Aminopeptidase inhibitors : 3-(2, 6-diethylphenyl)-2,4(1H, 3H)-quinazolinedione and N-(2, 6-diethylphenyl)-2-amini-4H-3, 1-benzoxazin-3-one"Heterocycles. 55. 1433-1438 (2001)

[文献書誌] S.Akashi: "Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition"Int Immunol.. 13・12. 1595-1599 (2001)

[文献書誌] Y.Fukase: "New Efficient Route for Synthesis of Lipid A by using Affinity Separation"Synlett. 11. 1693-1698 (2001)

[文献書誌] Y.Shigeri: "Effects of threo-β-hydroxyaspartate derivatives on excitatory amino acid transporters (EAAT4 and EAAT5)"J.Neurochem. 79・2. 297-302 (2001)

[文献書誌] M.Ebisawa: "Novel retinoidal tropolone derivatives. Bioisosteric relationship of tropolone ring with benzoic acid moiety in retinoid structure"Chem.Pharm.Bull.. 49・4. 501-503 (2001)

[文献書誌] Y.Endo: "Structure-Activity study of retinoid agonists bearing substituted dicarba-closo-dodecaborane. Relation between retinoidal acitivity and conformation of two aromatic nuclei"Bioorg.Med.Chem.Lett.. 11・10. 1307-1311 (2001)

[文献書誌] T.Yamauchi: "Replenishment of the fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7・8. 941-946 (2001)

[文献書誌] T.Yamauchi: "Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108・7. 1001-1013 (2001)

[文献書誌] H.Torigoe: "Promotion of triplex formation by 2'-O, 4'-C-methilene bridged nucleic acid (2', 4'-BNA) modification : thermodynamic and kinetic studies"Nucleosides Nucleotides Nucleic Acids.. 20・4-7. 1235-1238 (2001)

[文献書誌] S.Obika: "2'-O, 4'-C-Methylene bridged nucleic acid (2', 4'-BNA ) : synthesis and tripllex-forming properties"Bioorg.Med.Chem.. 9・4. 1001-1011 (2001)

[文献書誌] S.Obika: "A 2', 4'-Bridged Nucleic Acid Containing 2-Pyridone as a Nucleobase : Efficient Recognition of a C・G Interruption by Triplex Formation with a Pyrimidine Motif"Angew.Chem.Int.Ed.Engi.. 40・11. 2079-2081 (2001)

[文献書誌] 石川智久: "ゲノム創薬に何が必要か?"現代化学. 11月. 56-60 (2001)

[文献書誌] T.Ikemoto: "Properties of Ca^<2+> release induced by clofibiric acid in the sarcoplasmic reticulum of mouse skeletal muscle fibres"Br.J.Pharmacol.. 134・4. 719-728 (2001)

[文献書誌] K.Nakamura: "Prostaglandin EP3 receptor protein in serotonin and catecholamine cell groups : a double immunofluorescence study in the rat brain"Neuroscience. 103・3. 763-775 (2001)

[文献書誌] S.Akiyoshi: "Targets of transcriptional regulation by transforming growth factor-beta : Expression profile analysis using oligonucleotide arrays"Jpn.J.Cancer Res.. 92・3. 257-268 (2001)

[文献書誌] Y.Hippo: "Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes"Cancer Res.. 61・3. 889-895 (2001)

[文献書誌] T.Kamimoto: "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1"J.Biol.Chem.. 276・40. 37520-37528 (2001)

[文献書誌] T.Kojima: "Cloning of Human PRP4 Reveals Interaction with Clk1"J.Biol.Chem.. 276・34. 32247-32256 (2001)

[文献書誌] M.Osada: "Regulatory Domain of Protein Stability of Human P51/TAP63, a P53 Homologue"Biochem.& Biophys.Res.Comm.. 283・5. 1135-1141 (2001)

[文献書誌] S.Aritani: "Dual roles of RNA helicase A in CREB-dependent transcription"Mol.Cell Biol.. 21・14. 4460-4469 (2001)

[文献書誌] H.R.Ueda: "Robust oscillations within the interlocked feedback model of drosophila circadian rhythm"J.Theo.Biol.. 210・4. 401-406 (2001)

[文献書誌] S.Maekawa: "Localization of neuronal growth-associated, microtubule-destabilizing factor SCG1O in brain-derived raft membrane microdomains"J.Biochem.. 129・5. 691-697 (2001)

[文献書誌] M.Chida: "[^<18>F] labeled diacylglycerol analogue as potential agent to trace myocardial phosphoinositide metabolism"Nucl.Med.Biology. 28・7. 815-819 (2001)

[文献書誌] T.Valdes-Gonzalez: "Neuropeptides interact with glycolipid receptors : A surface plasmon resonance study"Peptides. 22・7. 1099-1106 (2001)

[文献書誌] H.Tsukada: "Age differences in muscarinic cholinergic receptor assayed with (+)N-[(11)C]methyl-3-piperidyl benzilate in the brains of consious monkeys"Synapse. 41・3. 248-257 (2001)

[文献書誌] T.Kakiuchi: "Age-related changes in muscarinic cholinergic receptors in the living brain : a PET study using N-[^<11>C]methyl-4-piperidyl benzilate combined with cerebral blood flow measurement in conscious monkeys"Brain Res.. 916・1-2. 22-31 (2001)

[文献書誌] H.Tsukada: "Effects of aging on 5-HT(1A) receptors and their functional response to 5-HT(1a) agonist in the living brain : PET study with [carbonyl-(11)C]WAY-100635 in conscious monkeys"Synapse. 42・4. 242-251 (2001)

[文献書誌] T.Kakiuchi: "Effects of aging on serotonin transporter availability and its response to fluvoxamine in the living brain : PET study with"Synapse. 40・3. 170-179 (2001)

2001 年度実績報告書

鈴木正昭岐阜大学, 工学部, 教授 (90093046)