JPS63215697A - Relaxing peptide and production thereof - Google Patents
Relaxing peptide and production thereofInfo
- Publication number
- JPS63215697A JPS63215697A JP62048431A JP4843187A JPS63215697A JP S63215697 A JPS63215697 A JP S63215697A JP 62048431 A JP62048431 A JP 62048431A JP 4843187 A JP4843187 A JP 4843187A JP S63215697 A JPS63215697 A JP S63215697A
- Authority
- JP
- Japan
- Prior art keywords
- leu
- met
- phe
- odmsp
- arg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 15
- 230000002040 relaxant effect Effects 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- -1 methoxybenzyloxycarbonyl Chemical group 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 5
- 239000004475 Arginine Substances 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 4
- HVNQCDIUFGAINF-STQMWFEESA-N (2s)-2-amino-n-[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]-4-methylpentanamide Chemical group CC(C)C[C@H](N)C(=O)N[C@H](C(N)=O)CC1=CC=CC=C1 HVNQCDIUFGAINF-STQMWFEESA-N 0.000 abstract description 2
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 abstract description 2
- 239000002249 anxiolytic agent Substances 0.000 abstract description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract description 2
- 108010062232 leucyl-phenylalanine amide Proteins 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 abstract 1
- FORGMRSGVSYZQR-YFKPBYRVSA-N L-leucinamide Chemical group CC(C)C[C@H](N)C(N)=O FORGMRSGVSYZQR-YFKPBYRVSA-N 0.000 abstract 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 abstract 1
- OBSIQMZKFXFYLV-QMMMGPOBSA-N L-phenylalanine amide Chemical group NC(=O)[C@@H](N)CC1=CC=CC=C1 OBSIQMZKFXFYLV-QMMMGPOBSA-N 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract 1
- 239000003729 cation exchange resin Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003387 muscular Effects 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 210000003205 muscle Anatomy 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZERULLAPCVRMCO-UHFFFAOYSA-N sulfure de di n-propyle Natural products CCCSCCC ZERULLAPCVRMCO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000037020 contractile activity Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
（発明の口約）
本発明は種々の平滑筋および骨格筋に対し、弛緩作用を
示す新規なペプチドおよびその製造方法に関する。さら
に詳しくは、一般式％式％
アラニン、Ｍｅｔはメチオニン、 Ｐｒｏはプロリン、
Ｌｅｕはロイシン、Ａｒｇはアルギニン・であり、Ｘ
はＬｅｕ−Ｐｈｅ−ＮＨ２（ここでＰｈｅはフエ二一ル
アラニンでありＮ１（２はアミノ酸のカルボキシル基を
アミド化したものである。（以下同じ） ） 、 Ｌｅ
ｕ、 Ｌｅｕ−Ｎｌ２． 、 Ｐｈｅ−Ｎｌ２のいずれ
かを示す。）で表わされる弛緩作用を示ず薬理的に有用
なペプチドおよびその製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Statement of the Invention) The present invention relates to a novel peptide that exhibits a relaxing effect on various smooth muscles and skeletal muscles, and a method for producing the same. For more details, see the general formula % formula % alanine, Met is methionine, Pro is proline,
Leu is leucine, Arg is arginine, and X
is Leu-Phe-NH2 (where Phe is phenylalanine and N1 (2 is the amidated carboxyl group of an amino acid (the same applies hereinafter)), Le
u, Leu-Nl2. , Phe-Nl2. ) and a method for producing the same.
（従来の技術）
本発明者は、これまでに軟体動物起源の神経ペプチド
Ｐｈｅ−Ｍｅｔ−Ａｒｇ−Ｐｈｅ−Ｎｌ（２の各種筋肉
に対する収縮作用及び弛緩作用の発現と化学構造の相関
性を研究する目的で、多くのアナローブを化学的に合成
し活性と化学構造の相関性を詳細にしてきた。(Prior Art) The present inventor has previously discovered neuropeptides derived from molluscs.
Phe-Met-Arg-Phe-Nl (2) In order to study the correlation between the expression of contraction and relaxation effects on various muscles and the chemical structure, we chemically synthesized many analogs and investigated the correlation between activity and chemical structure. have been detailed.
（発明の構成）
この結果、Ｐｈｅ−Ｍｅｔ−Ａｒｇ−Ｐｈｅ−Ｎｌ２は
収縮と弛緩作用を同時に持つことが知られており、作用
濃度に応じておのおのの作用を発現する。(Structure of the Invention) As a result, Phe-Met-Arg-Phe-Nl2 is known to have both contraction and relaxation effects at the same time, and exhibits each effect depending on the active concentration.
このことに対して、収縮活性あるいは弛緩活性それぞれ
の活性を発現するための化学構造が明らかとなった。In response to this, the chemical structure for expressing contractile activity or relaxant activity has been clarified.
すなわち、収縮活性には、Ｎ末端に疎水性部分が結合す
ることが必須であり、弛緩活性には、Ｎ末端部分の疎水
性とアミノ酸残基の側鎖鎖長の適当なバランスが必要で
あることが判明した。以上の研究過程において、Ａｌａ
−Ｍｅｔ−Ｐｒｏ−Ｍｅ ｔ−Ｌｅｕ−Ａｒｇ−Ｘで表
わされるペプチドが、弛緩作用を示すことを見出した。That is, binding of a hydrophobic moiety to the N-terminus is essential for contractile activity, and an appropriate balance between the hydrophobicity of the N-terminus and the side chain length of the amino acid residue is required for relaxation activity. It has been found. In the above research process, Ala
It has been found that a peptide represented by -Met-Pro-Me t-Leu-Arg-X exhibits a relaxing effect.
持にＡｌａ−Ｍｅ ｔ−Ｐｒｏ−Ｍｅ ｔ−Ｌｅｕ−Ａ
ｒｇ−Ｌｅｕ−Ｎｌ（２で示されるヘプタペプチドアミ
ドは、１０−’Ｍの低濃度においても強い弛緩作用を示
すことが判明（７な。このような類似のペプチドは貝類
の筋肉中にも存在しているものと思われる。さらに、本
発明のペプチドは、水中で簡便に製造できることをも、
見出した。すなわぢＬｅｕ−Ａｒｇ−Ｘと水溶性活性エ
ステルであるｐＭＺ−Ｍｅ ｔ−ＯＤＭＳＰ（ここでｐ
ＭＺはｐ−メトキシベンジルオキジカルボユルオキジ基
であり、ＯＤＭＳＰはｐ−ジメチルスルホニオフェニル
基を示す１．）とをｐ Ｏ７，０〜８．０の中性から弱
塩基性の条件下で縮合させて反応系より析出するｐＭＺ
−Ｍｅ ｔ−Ｌｃｕ−Ａｒｇ−ＸＧ単ＪＩｍし、エチル
メチルスルフィド存在下、トリフルオロ酢酸の処理によ
ってｐ１＋４Ｚ基を脱離させる。さらに、同様に水中に
てｐＨ７，０〜８．０の条件下、水溶性活性エステルで
あるｐＭＺ−Ａｌａ−Ｍｅｔ−Ｐｒｏ−ＯＤＭＳＰとを
反応させ、ｐＭＺ−Ａ Ｉ ａ−Ｍｅ ｔ−Ｐｒｏ−Ｍ
ｅ ｔ−Ｌｅｕ−Ａｒｇ−Ｘを得る。この反応系から結
晶として析出する保護ペプチドはさらにエチルメチルス
ルフィド存在下トリフルオロ酢酸処理することにより目
的の薬理的に有用であるペプチドがＡｒｇ側鎖無保護で
簡便かつ高収率にて合成できる。Ala-Me t-Pro-Me t-Leu-A
The heptapeptide amide represented by rg-Leu-Nl (2) was found to exhibit a strong relaxing effect even at a low concentration of 10-'M (7).Such similar peptides also exist in the muscles of shellfish. Furthermore, the peptide of the present invention can be easily produced in water.
I found it. In other words, Leu-Arg-X and the water-soluble active ester pMZ-Me t-ODMSP (here p
MZ is a p-methoxybenzyloxycarboylokidi group, and ODMSP is a p-dimethylsulfoniophenyl group.1. ) and pMZ precipitated from the reaction system by condensation under neutral to weakly basic conditions with pO7.0 to 8.0.
-Met-Lcu-Arg-XG is isolated and the p1+4Z group is removed by treatment with trifluoroacetic acid in the presence of ethyl methyl sulfide. Furthermore, pMZ-Ala-Met-Pro-ODMSP, which is a water-soluble active ester, was reacted with pMZ-Ala-Met-Pro-ODMSP in water at a pH of 7.0 to 8.0.
e t-Leu-Arg-X is obtained. The protected peptide precipitated as crystals from this reaction system is further treated with trifluoroacetic acid in the presence of ethyl methyl sulfide, whereby the desired pharmacologically useful peptide can be synthesized easily and in high yield without protection of the Arg side chain.
（実施例）
以下実施例において本発明を具体的に説明するが、本発
明は実施例により限定されろものではない。(Examples) The present invention will be specifically explained in Examples below, but the present invention is not limited to the Examples.
合成例
Ａ ｌ ａ−Ｍｅ ｔ−Ｐｒｏ−Ｍｅ ｔ−Ｌｅｕ−Ａ
ｒｇ−Ｌｅｕ−Ｎｌ２の合成１ ） Ｚ−Ｌｅｕ−Ａｒ
ｇ（ＮＯ２）−Ｌｅｕ−ＮＩＩ２の合成法Ａｒｇ（ＮＯ
２）−Ｌｅｕ−Ｎｌ２− ｌｌＣｌ （３、８２ｇ
。Synthesis example A l a-Me t-Pro-Me t-Leu-A
Synthesis of rg-Leu-Nl2 1) Z-Leu-Ar
Synthesis method of g(NO2)-Leu-NII2 Arg(NO2)-Leu-NII2
2)-Leu-Nl2-llCl (3,82g
.
１０ｍ＋＋＋ｏｌ） （Ａｒｇ（ＮＯ２）はニトロ化
アルギニシを示す）と、Ｎ−メチルモルホリン１，１ｍ
ｌをクロロホルム２０ｍ１に溶解した溶液をＺ−Ｌｅｕ
−Ｏｆｆ （２，６５ｇ、 １０ｍｍｏｌ） （Ｚ
はベンジルオキシカルボニル基を示す）と、トリエチル
アミン１．４ｍｌおよびエチルクロロホルメー） １
ｍ ｌとの混合物を一５℃に冷却して加える。０℃にて
２時間反応させ、さらに室温で一夜放置し、反応混合物
を減圧濃縮した。残さを氷水に投入し、析出する沈殿物
をろ過し、２％塩酸、水、４％重炭酸プ何・リウムで洗
浄し、酢酸エチ°ルで再結晶する。10m+++ol) (Arg(NO2) indicates nitrated arginine) and N-methylmorpholine 1,1m
A solution of Z-Leu dissolved in 20ml of chloroform
-Off (2.65g, 10mmol) (Z
indicates benzyloxycarbonyl group), triethylamine 1.4 ml and ethyl chloroforme) 1
ml of the mixture is cooled to -5°C and added. The reaction mixture was allowed to react at 0° C. for 2 hours, and then allowed to stand at room temperature overnight, and the reaction mixture was concentrated under reduced pressure. The residue is poured into ice water, and the precipitate is filtered, washed with 2% hydrochloric acid, water, and 4% sodium bicarbonate, and recrystallized from ethyl acetate.
収量４．１２ｇ（７２％）〔ａ〕。＝−１８゜（ＣＩ、
ＤＭＦ）、融点１８５〜１８９℃ＴＬＣで１スポツトを
与えた。Yield: 4.12 g (72%) [a]. =-18° (CI,
DMF), melting point 185-189°C TLC gave 1 spot.
２ ） Ｌｅｕ−Ａｒｇ−Ｌｅｕ−Ｎｌ２ ・２ＡｃＯ
Ｈの合成Ｚ−Ｌｅｕ−Ａｒｇ（ＮＯ２）−Ｌｅｕ−Ｎｌ
（２（１，０３ｇ 、 １．８ｍｍｏ Ｉ ）を酢
酸５ｍｌに懸濁させ、パラタウ１１ブラツク約０．５ｇ
を加えて攪拌しながら水素を２１時間通した。反応液を
減圧下濃縮（７、残さにエーテルを加えて結晶化した、
。2) Leu-Arg-Leu-Nl2 ・2AcO
Synthesis of HZ-Leu-Arg(NO2)-Leu-Nl
(2 (1,03 g, 1.8 mmol I) was suspended in 5 ml of acetic acid, and about 0.5 g of Paratau 11 black was suspended in 5 ml of acetic acid.
was added and hydrogen was passed through the mixture for 21 hours while stirring. The reaction solution was concentrated under reduced pressure (7, ether was added to the residue to crystallize it,
.
収量０．９６ｇ （９０％） 融点２１４〜２１６℃Ｃ
ａ〕’ｏ＝−１８° （ＣＩ、ＤＭＦ）ＴＬＣで１スポ
ツトを与えた。Yield 0.96g (90%) Melting point 214-216℃
a]'o=-18° (CI, DMF) 1 spot given by TLC.
３ ） ｐＭＺ−Ｍｅｔ−Ｌｅｕ−Ａｒｇ−Ｌｅｕ−Ｎ
［（２・＾ｃＯＩｌの合成Ｌｅｕ−Ａｒｇ−Ｌｅｕ−Ｎ
Ｈ２・ ２人ｃＯＨ（０，２５ｇ。3) pMZ-Met-Leu-Arg-Leu-N
[(2・^cOIl synthesis Leu-Arg-Leu-N
H2・2 people cOH (0.25g.
０ 、４２ｍｍｏｌ）を純水５ｍｌに溶解し、１Ｍ炭酸
すトリウムでｐ Ｈを７．５とし、攪拌（７ながらｐＭ
Ｚ−Ｍｅｔ−ＯＤＭＳＰ Ｏ、５ｇを加えた。８時間室
温で攪拌し、析出する白色結晶全ろ取し、メタノールで
再結晶した。0, 42 mmol) in 5 ml of pure water, adjusted the pH to 7.5 with 1M sodium carbonate, and stirred (at 7 pM
5 g of Z-Met-ODMSPO was added. The mixture was stirred at room temperature for 8 hours, and all precipitated white crystals were collected by filtration and recrystallized from methanol.
収量０−５８ｇ （７０％）［（ｒ）ｎ＝ ２２°
（ＣＩ、ＤＭＦ） 融点１９５℃（分解）ＴＬＣで
１スポットを与えた。Yield 0-58g (70%) [(r)n=22°
(CI, DMF) Melting point 195°C (decomposition) TLC gave one spot.
４ ） Ｍｅｔ−Ｌｅｕ−Ａｒｇ−Ｌｅｕ−ＮＨ２−２
ＴＦＡの合成ｐＭＺ−八１ｅへ−Ｌｅｕ−Ａｒｇ−Ｌｅ
ｕ−ＮＨ２−Ａｃ０Ｉ（（０、８２ｇ 、 １ ｍｍ
ｏｌ）にエチルメチルスルフィド１ ｍ ｌおよびトリ
フルオロ酢酸（ＴＦＡ）５ｍｌを加えて室温にて２時間
放置しｔコ。反応液を減圧上濃縮し、エーテルを加えて
結晶化した。4) Met-Leu-Arg-Leu-NH2-2
Synthesis of TFA to pMZ-81e-Leu-Arg-Le
u-NH2-Ac0I ((0, 82 g, 1 mm
1 ml of ethyl methyl sulfide and 5 ml of trifluoroacetic acid (TFA) were added to the mixture, and the mixture was left at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ether was added for crystallization.
収量０．６８ｇ （８９％） 融点１４５℃（分ＪＡＷ
） Ｃ’ａ ］ Ｄ＝−１４° （ＣＩ、ＭｅＯＨ
）、ＴＬＣで１スポットを与左た。Yield 0.68g (89%) Melting point 145℃ (min JAW
) C'a ] D=-14° (CI, MeOH
), won one spot on TLC.
５ ） ｐＭＺ−Ａｌａ−Ｍｅｔ−Ｐｒｏ−Ｍｅｔ−
Ｌｅｕ−八ｒｇ−Ｌｃｕ−Ｎｉｌ。5) pMZ-Ala-Met-Pro-Met-
Leu-8rg-Lcu-Nil.
・ＴＦＡの合成
Ｍｅｔ−Ｌｅｕ−Ａｒｇ−Ｌｅｕ−ＮＨ２・ ２ＴＦＡ
Ｏ、７６８ｇ（１ｍｍｏｌ）を水１０ｍ１に溶解
させ、１Ｍ炭酸ソーダにてｐＨ７，２とし、ｐＭＺ−人
１ ａ −ＦＩＩＧ Ｌ −Ｉ’ｒｏ−ＯＤＭＳＰ １
、 Ｏｇを水５ｍｌに溶解させｔ：溶液を室温で攪拌
しながら加えた。８時間反応させたのち、析出する結晶
物をろ取し、４％クエン酸、水、４９６重炭酸すトリウ
ムおよび水で洗浄（７、メタノールで再結晶して目的物
を得た。・Synthesis of TFA Met-Leu-Arg-Leu-NH2・2TFA
Dissolve 768 g (1 mmol) of O in 10 ml of water, adjust the pH to 7.2 with 1 M sodium carbonate, and prepare pMZ-FIIG L -I'ro-ODMSP 1.
, Og was dissolved in 5 ml of water and the solution was added with stirring at room temperature. After reacting for 8 hours, the precipitated crystals were collected by filtration, washed with 4% citric acid, water, sodium 496 bicarbonate, and water (7. Recrystallized with methanol to obtain the desired product.
収量０．４６ｇ （５８％） 融点１９０℃（分解）〔
α）ｎ＝−２１° （ＣＩ、ＤＭＦ）ＴＬＣで１スポッ
トを与えた。Yield: 0.46g (58%) Melting point: 190°C (decomposed) [
α) n=−21° (CI, DMF) One spot was given by TLC.
６ ） Ａｌａ−Ｍｅｔ−Ｐｒｏ−Ｍｅｔ−Ｌｅｕ−Ａ
ｒｇ−Ｌｅｕ−Ｎ［ｒ２ ・２ＴＦ人の合成
ｐＭＺ−Ａｌａ−Ｍｅｔ−Ｐｒｏ−Ｍｅｔ−Ｌｅｕ−Ａ
ｒｇ−Ｌｅｕ−Ｎ［（２・ＴＦＡ０．５ｇにエチル、メ
チルスルフィド０・５ｍｌとトリフルオロ酢酸５ｍｌを
加え室温で２時間放置した。反応液を減圧上濃縮し残さ
を水に溶解させ陽イオン交換樹脂を通し、目的物のフラ
クションを集めた。この溶液を用いて生理活性試験を行
った。6) Ala-Met-Pro-Met-Leu-A
rg-Leu-N[r2 2TF human synthesis pMZ-Ala-Met-Pro-Met-Leu-A
rg-Leu-N[(2.0.5 ml of methyl sulfide and 5 ml of trifluoroacetic acid were added to 0.5 g of TFA and allowed to stand at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water for cation exchange. A fraction of the target product was collected through the resin, and a physiological activity test was performed using this solution.
生理活性試験
二枚貝の足糸前とう川筋を用いて１０−４Ｍアセデルコ
リン溶液を作用させ、一度筋肉を収縮させたのち、各種
ペプチド溶液を作用させ、その弛緩作用を観察した。そ
の結果、
Ａｌａ−Ｍｅｔ−Ｐｒｏ−Ｍｅｔ−Ｌｅｕ−八ｒｇ−Ｌ
ｅｕ−Ｐｈｅ−Ｎｔ（２は１０−’Ｍで弛緩作用を示し
Ａ ｌ ａ−Ｍｅ ｔ−Ｉ’ｒｏ−ＭＱｔ−Ｌｅｕ−Ａ
ｒｇ−Ｌｅｕ−ＮＨ２は１０−９Ｍで弛緩作用を示した
。Physiological activity test A 10-4M acedercholine solution was applied to the pre-byssus muscle of a bivalve to cause the muscle to contract, and then various peptide solutions were applied to the muscle and its relaxing effect was observed. As a result, Ala-Met-Pro-Met-Leu-8rg-L
eu-Phe-Nt (2 exhibits a relaxing effect at 10-'M
rg-Leu-NH2 showed a relaxing effect at 10-9M.
（発明の効果）
実施例記載のごとく本ペプチドには、筋肉弛緩作用がみ
られる。よって本ペプチドには薬理効果が期待されるも
のである。(Effects of the Invention) As described in the Examples, this peptide has a muscle relaxing effect. Therefore, this peptide is expected to have pharmacological effects.
Claims (2)
ｇ−Ｘで表わされる弛緩ペプチド （ここでＡｌａはアラニン、Ｍｅｔはメチオニン、Ｐｒ
ｏはプロリン、Ｌｅｕはロイシン、Ａｒｇはアルギニン
であり、ＸはＬｅｕ−Ｐｈｅ−ＮＨ＿２（ここでＰｈｅ
はフェニルアラニンでありＮＨ＿２はアミノ酸のカルボ
キシル基をアミド化したものである。（以下同じ））、
Ｌｅｕ、Ｌｅｕ−ＮＨ＿２、、Ｐｈｅ−ＮＨ＿２のいず
れかを示す。）(1) Ala-Met-Pro-Met-Leu-Ar
Relaxing peptide represented by g-X (where Ala is alanine, Met is methionine, Pr
o is proline, Leu is leucine, Arg is arginine, and X is Leu-Phe-NH_2 (where Phe
is phenylalanine, and NH_2 is an amidated carboxyl group of an amino acid. (same as below)),
Indicates either Leu, Leu-NH_2, or Phe-NH_2. )
Ｍｅｔをはメチオニン、Ｐｒｏはプロリン、Ｌｅｕはロ
イシン、Ａｒｇはアルギニンであり、ＸはＬｅｕ−Ｐｈ
ｅ−ＮＨ＿２（ここでＰｈｅはフェニルアラニンであり
ＮＨ＿２はアミノ酸のカルボキシル基をアミド化したも
のである。（以下同じ））、Ｌｅｕ、Ｌｅｕ−ＮＨ＿２
、Ｐｈｅ−ＮＨ＿２のいずれかを示す。）と、ｐＭＺ−
Ｍｅｔ−ＯＤＭＳＰ（ここでｐＭＺはｐ−メトキシベン
ジルオキシカルボニルオキシ基であり、ＯＤＭＳＰはｐ
−ジメチルスルホニオフェニル基を示す。）とを水中に
てｐＨ７．０〜８．０にて反応させて得られた保護ペプ
チドを脱保護し、さらに水中で、ｐＨ７．０〜８．０の
条件下、ｐＭＺ−Ａｌａ−Ｍｅｔ−Ｐｒｏ−ＯＤＭＳＰ
（ｐＭＺ、ＯＤＭＳＰは上記定義どおり）を反応させ、
さらにｐＭＺ基を酸により脱離させることを特徴とする
弛緩ペプチドの製造方法。(2) Leu-Arg-X (where Ala is alanine,
Met is methionine, Pro is proline, Leu is leucine, Arg is arginine, and X is Leu-Ph.
e-NH_2 (here, Phe is phenylalanine and NH_2 is the amidated carboxyl group of an amino acid (the same applies hereinafter)), Leu, Leu-NH_2
, Phe-NH_2. ) and pMZ-
Met-ODMSP (where pMZ is p-methoxybenzyloxycarbonyloxy group and ODMSP is p-
- indicates a dimethylsulfoniophenyl group. ) in water at pH 7.0 to 8.0 to deprotect the obtained protected peptide, and further in water at pH 7.0 to 8.0, pMZ-Ala-Met-Pro -ODMSP
(pMZ and ODMSP are as defined above),
A method for producing a relaxed peptide, which further comprises removing the pMZ group with an acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62048431A JPS63215697A (en) | 1987-03-02 | 1987-03-02 | Relaxing peptide and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62048431A JPS63215697A (en) | 1987-03-02 | 1987-03-02 | Relaxing peptide and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63215697A true JPS63215697A (en) | 1988-09-08 |
Family
ID=12803161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62048431A Pending JPS63215697A (en) | 1987-03-02 | 1987-03-02 | Relaxing peptide and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63215697A (en) |
-
1987
- 1987-03-02 JP JP62048431A patent/JPS63215697A/en active Pending
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