JP2013227234A - Cgrp応答性促進剤 - Google Patents
Cgrp応答性促進剤 Download PDFInfo
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- JP2013227234A JP2013227234A JP2012098963A JP2012098963A JP2013227234A JP 2013227234 A JP2013227234 A JP 2013227234A JP 2012098963 A JP2012098963 A JP 2012098963A JP 2012098963 A JP2012098963 A JP 2012098963A JP 2013227234 A JP2013227234 A JP 2013227234A
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Abstract
【解決手段】下記式(I)で表されるリグナン類を有効成分とする細胞のCGRP応答性促進剤(式(I)中、R1は水素原子又はアルコキシ基を示し、R2、R3及びR4は、同一又は異なって、アルコキシ基を示す)。
【化1】
【選択図】なし
Description
(1)下記式(I)
で表されるリグナン類を有効成分とする細胞のCGRP応答性促進剤。
(2)R1が水素原子又は炭素数1〜3のアルコキシ基であり、且つR2、R3及びR4がメトキシ基である、(1)記載の促進剤。
(3)上記細胞が血管平滑筋細胞である、(1)又は(2)記載の促進剤。
(4)上記式(I)で表される化合物を有効成分とする皮膚循環改善剤。
(5)上記式(I)で表される化合物を有効成分とする血行促進剤。
(6)上記式(I)で表される化合物を有効成分とする皮膚代謝改善剤。
(7)上記式(I)で表される化合物を有効成分とする創傷治癒促進剤。
(8)R1が水素原子又は炭素数1〜3のアルコキシ基であり、且つR2、R3及びR4がメトキシ基である、(4)〜(7)のいずれか1に記載の剤。
(9)細胞のCGRP応答性を促進する方法であって、CGRP受容体を有し且つCGRP応答性を促進させたい細胞を、(1)〜(3)のいずれか1に記載のCGRP応答性促進剤の存在下で培養する工程を含む、方法。
(10)上記細胞が血管平滑筋細胞である(9)記載の方法。
本発明による細胞のCGRP応答性促進剤は、CGRPにより惹起される細胞におけるこれらの一連のプロセスを促進し得る。例えば、本発明のCGRP応答性促進剤の作用としては、CGRPとその受容体との結合の促進、Gタンパク質活性の増強、アデニレートシクラーゼ活性の増強、細胞内cAMPの増加、プロテインキナーゼA活性の増強、NO産生又はcGMP活性の増強、及びK+チャネル開口促進等が挙げられる。好ましくは、「細胞のCGRP応答性」は、CGRPにより引き起こされる細胞内cAMPの増加の程度を指標として決定され得る。従って、本発明のCGRP応答性促進剤は、好ましくは、CGRPにより惹起される細胞内cAMPの増加を促進する。
あるいは、当該「細胞」は、上記で挙げた細胞の細胞片又は細胞分画物であってもよく、上記で挙げた細胞を含む組織又は上記で挙げた細胞に由来する培養物であってもよい。
上記飲食品等における式(I)リグナン類の含有量は、0.00001〜100質量%とするのが好ましく0.00002〜75質量%とするのがより好ましく、0.00005〜50質量%とするのがさらに好ましく、0.0001〜30質量%とするのがさらにより好ましく、0.0002〜10質量%とするのがなお好ましい。
一態様において、当該投与は、健康促進又は美容目的での皮膚循環の改善、皮膚代謝改善、又は血行促進を企図して、非治療的に行われる。
リグナン類による細胞のCGRP応答性促進効果を調べた。
1.方法
(1)細胞培養
正常ヒト冠状動脈平滑筋細胞(HCASMC;クラボウ社、細胞lot# 01272)を増殖用培地(基礎培地HuMedia-SB2 500mlにFBS 25ml、hEGF 0.5ml、hFGF−B 0.5ml、インスリン0.5ml、抗菌剤0.5mlを添加したもの;クラボウ社)で培養した。継代には0.025%トリプシン/0.01%EDTAを用いた。
正常ヒト冠状動脈平滑筋細胞(HCASMC)を4000個/cm2の密度で増殖用培地を用いて48ウェルプレートに播種し、翌日分化用培地(基礎培地HuMedia-SB2 500mlにFBS 5ml、ヘパリン0.5ml、抗菌剤0.5mlを添加したもの;クラボウ社)に交換した。培地を1日おきに交換して7日間培養し、CGRP応答性の測定に供した。
細胞を、ホスホジエステラーゼ阻害剤(PDI)であるIBMX(3-Isobutyl-1-methylxanthine、500μM;シグマ社)、Ro-20-1724(100μM;和光純薬工業株式会社)、及び所定の濃度の下記に示すリグナン類化合物を含む基礎培地(Humedia-SB2;クラボウ社)で2回洗浄し、さらに同培地を200μl添加して37℃にて60分間培養し、細胞内に阻害剤を浸透させた。培地を除去して、同じ濃度の下記に示すリグナン類化合物、0.5nM CGRP、PDIを含む基礎培地を添加し、15分間37℃にて培養した。反応の停止は、cAMP測定EIAキット(cAMP EIA(non-acetylation);GEヘルスケアバイオサイエンス株式会社)に付属の細胞溶解液を添加することにより行い、取扱説明書に記載の方法に従って細胞内cAMP濃度([cAMP]i)を測定した。化合物のCGRP応答性促進能は、0.5nM CGRPのみで刺激したときの[cAMP]iを基準(コントロール)とし、これに対する百分率をImprove Indexとして表した。
(4)試験化合物
試験には、以下のリグナン類化合物TD−1及びTD−2を用いた。これらの化合物は、特開平10−175861号公報に記載の方法に基づいて、以下の手順で調製した。アスナロ乾燥粉砕物(180g)をエタノール1Lに浸漬し、室温において時々攪拌しながら7日間抽出を行い、得られた抽出液を濾過し、濾液を5℃において3日間静置した後、再度濾過し、上澄みを得た。次に溶媒を留去して得られた残渣(2.4g)をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル、CHCl3:CH3OH、H2O:CH3OH)、高速液体クロマトグラフィー(YMC−ODS S−10、YMC社製)に供することによって調製した(収量:TD−1 21mg、TD−2 25mg)。
CGRP応答性の測定結果を図1A及びBに示す。Improve Index 100% は、1189.3 fmol/wellの[cAMP]iに相当する。化合物TD−1及びTD−2は、濃度依存的に細胞のCGRP応答性を有意に促進した(Dunnett検定、N=3)。
化合物の添加条件を様々に変更して細胞のCGRP応答性を調べた。
1.方法
実施例1と同様の条件でHCASMC(クラボウ社、細胞lot# 01272)を調製した。その後、表1に記載の条件で培養物にホスホジエステラーゼ阻害剤(PDI)、試験化合物(TD−1又はTD−2、100nM)、及び/又はCGRP(0.5nM)を添加して培養し、その後、実施例1と同様の方法で細胞のCGRP応答性を測定した。
CGRP応答性の測定結果を図2に示す。Improve Index 100% は、1189.3 fmol/wellの[cAMP]iに相当する。CGRP刺激時に試験化合物を添加することにより、Improve Indexは増加した(条件2〜3)。一方、CGRP非存在下ではImprove Indexは有意に低かった(条件4)ことから、試験化合物による作用は、CGRPを代替するもの(例えば、CGRP受容体アゴニスト)ではなく、CGRPとその受容体との結合により惹起される一連の応答を促進するものであることが示された。
Claims (10)
- 下記式(I)
で表されるリグナン類を有効成分とする細胞のCGRP応答性促進剤。 - R1が水素原子又は炭素数1〜3のアルコキシ基であり、且つR2、R3及びR4がメトキシ基である、請求項1記載の促進剤。
- 前記細胞が血管平滑筋細胞である、請求項1又は2記載の促進剤。
- 下記式(I)
で表されるリグナン類を有効成分とする皮膚循環改善剤。 - 下記式(I)
で表されるリグナン類を有効成分とする血行促進剤。 - 下記式(I)
で表されるリグナン類を有効成分とする皮膚代謝改善剤。 - 下記式(I)
で表されるリグナン類を有効成分とする創傷治癒促進剤。 - R1が水素原子又は炭素数1〜3のアルコキシ基であり、且つR2、R3及びR4がメトキシ基である、請求項4〜7のいずれか1項記載の剤。
- 細胞のCGRP応答性を促進する方法であって、CGRP受容体を有し且つCGRP応答性を促進させたい細胞を、請求項1〜3のいずれか1項記載のCGRP応答性促進剤の存在下で培養する工程を含む、方法。
- 前記細胞が血管平滑筋細胞である、請求項9記載の方法。
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PCT/JP2013/061932 WO2013161821A1 (ja) | 2012-04-24 | 2013-04-23 | Cgrp応答性促進剤 |
CN201380021733.7A CN104254328B (zh) | 2012-04-24 | 2013-04-23 | Cgrp应答性促进剂 |
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CN113018281A (zh) * | 2021-02-23 | 2021-06-25 | 中国人民解放军海军军医大学 | 一种Pellino1天然小分子抑制剂及其应用 |
CN113018281B (zh) * | 2021-02-23 | 2023-02-03 | 中国人民解放军海军军医大学 | 一种Pellino1天然小分子抑制剂及其应用 |
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RU2651766C2 (ru) | 2018-04-23 |
WO2013161821A1 (ja) | 2013-10-31 |
CN104254328B (zh) | 2016-08-17 |
EP2842558A1 (en) | 2015-03-04 |
EP2842558A4 (en) | 2015-10-28 |
CN104254328A (zh) | 2014-12-31 |
RU2014147020A (ru) | 2016-06-10 |
JP5923375B2 (ja) | 2016-05-24 |
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