DD276482A1 - METHOD FOR PRODUCING NEW CHOLECYSTOKININ SEQUENCES - Google Patents
METHOD FOR PRODUCING NEW CHOLECYSTOKININ SEQUENCES Download PDFInfo
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- DD276482A1 DD276482A1 DD32106788A DD32106788A DD276482A1 DD 276482 A1 DD276482 A1 DD 276482A1 DD 32106788 A DD32106788 A DD 32106788A DD 32106788 A DD32106788 A DD 32106788A DD 276482 A1 DD276482 A1 DD 276482A1
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- German Democratic Republic
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- acid residue
- met
- asp
- trp
- amino acid
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Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Antagonisten des Cholecystokinins der Formel I, AcylTyr(SE)XGlyTrpYNHAd I,in der Acyl z. B. Asparaginsaeure, Bernsteinsaeure oder eine Schutzgruppe, wie BOC oder Z sein kann, SE einen Sulfatesterrest bedeutet, X fuer Thr, Nle, Leu oder Met und Y fuer Met, Nle, Leu, Met-Asp, Nle-Asp oder Leu-Asp stehen. L-Trp in Formel I kann durch D-Trp ersetzt sein. Anwendungsgebiete der Erfindung sind die medizinische Forschung und die pharmazeutische Industrie.The invention relates to a process for the preparation of novel antagonists of cholecystokinin of the formula I, acylTyr (SE) XGlyTrpYNHAd I, in the acyl z. Aspartic acid, succinic acid or a protecting group such as BOC or Z, SE is a sulfate ester residue, X is Thr, Nle, Leu or Met and Y is Met, Nle, Leu, Met-Asp, Nle-Asp or Leu-Asp stand. L-Trp in formula I can be replaced by D-Trp. Areas of application of the invention are medical research and the pharmaceutical industry.
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von neuartigen acylierten Cholecystokininsequenzen der allgemeinen Formel,The invention relates to a process for the preparation of novel acylated cholecystokinin sequences of the general formula
in der Acyl einen Aminosäurerest, vorzugsweise Asparaginsäure, oder einer Carbonsäurerest, vorzugsweise Bernsteinsäure, oder eine in der Peptidchemie gebräuchliche Schutzgruppe wie t-Butyloxycayrbonyl (Boc) oder Benzyloxycarbonyl (Z) darstellt und SE einen Sulfatesterrest am Tyrosin bedeutet. X steht für einen Aminosäurerest, vorzugsweise Thr, Nie, Leu oder Met und Y für Met, Nie, Leu, Met-Asp, Nle-Asp oder Leu-Asp. Zur besseren enzymatischen Stabilität kann L-Trp durch D-Trp ersetzt worden. Derartige Peptide stellen neuartige, hochwirksame Antagonisten des Cholecystokinins dar und sind wertvolle Hilfsmittel für pharmakologische Untersuchungen. Anwendungsgebiete der Erfindung sind die medizinische Forschung und die pharmazeutische Industrie.in which acyl is an amino acid residue, preferably aspartic acid, or a carboxylic acid residue, preferably succinic acid, or a protecting group commonly used in peptide chemistry, such as t-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Z), and SE is a sulfate ester residue on tyrosine. X is an amino acid residue, preferably Thr, No, Leu or Met and Y is Met, No, Leu, Met-Asp, Nle-Asp or Leu-Asp. For better enzymatic stability, L-Trp may have been replaced by D-Trp. Such peptides are novel, highly effective antagonists of cholecystokinin and are valuable tools for pharmacological studies. Areas of application of the invention are medical research and the pharmaceutical industry.
und Niebcr, K.; Henklein, P.; Ott, T. und P.Oehme Z. gesamte inn. Med. 42 (1987) 501).and Niebcr, K .; Henklein, P .; Ott, T. and P.Oehme Z. Gesam inn. Med. 42 (1987) 501).
und J. D. Gardner 1983, Proc. Natl. Acad. Sei. 78 (1987) 0304) bzw. verkürzte oder cyclische Sequenzen des Cholecystokinins (Spanarkel et al., J. Biol. Chem. 258,674611983); M. Ch. Galas Am. J. Physiol. 254, G176 (1988) sowie R. N. Freidinger et al., Proc.and J.D. Gardner 1983, Proc. Natl. Acad. Be. 78 (1987) 0304) or truncated or cyclic sequences of cholecystokinin (Spanarkel et al., J. Biol. Chem. 258, 674611983); M. Ch. Galas Am. J. Physiol. 254, G176 (1988) and R.N. Freidinger et al., Proc.
19th. Europ. Peptid Syrrp. 1986 Porto Carras Griechenland, EP-PS 0132919).19th. Europ. Peptide syrrp. 1986 Porto Carras Greece, EP-PS 0132919).
EP-PS 170024).EP-PS 170024).
Ziel der Erfindung ist es, neuartige Antagonisten des Cholecystokinins auf Peptidbasis herzustellen, die eine höhere antagonistische Aktivität besitzen als die vergleichbaren bekannten Antagonisten.The aim of the invention is to produce novel antagonists of cholecystokinin peptide-based, which have a higher antagonist activity than the comparable known antagonists.
Der Erfindung liegt aie Aufgabe zugrunde. Verfahren zu entwickeln, nach denen sich neuartige Sequenzen des Cholecystokinins (CCK) mit antagonistischen Eigenschaften horsteilen lossen. Die Aufgabe wurde dadurch gelöst, daß C-terminal verkürzte Sequenzen synthetisiert wurden, denen die C-terminalen Aminosäuren Phenylalanin oder Phenylalanin und Asparaginsäure fehlen. Die endständige Aminosäure Y wurde in das 1 -Adamantylamid umgewandelt. Die so erhaltenen verkürzten CCK-Sequenzen zeigen überraschenderweise keinerlei agonistische Eigenschaften mehr, sind jedoch in der Lage, Cholecystokinin in Konzentrationen von 10~7 bis 10"' Mol/l zu hemmen. Die neuartigen Verbindungen wurden peptidchemisch in üblicher Weise entweder stufenweise od6r durch Fragmentkondensation unter Verwendung bekannter Schutzgruppen, beginnend vom BOC-Y-NH-Adamatyl, aufgebaut. Anschließend wird das geschützte Peptid von den Schutzgruppen befreit, acyliert und danach mit Pyridiniumacetylsulfat sulfatiert. Die Endreinigung erfolgt durch präparative HPLC an RP-18 isokratisch mit 25% Acetonitril/ 0,05n Ammoniumacetatlösung pH6,5The invention is based on the task. To develop methods according to which novel sequences of cholecystokinin (CCK) with antagonistic properties horsteilen. The object has been achieved by synthesizing C-terminally truncated sequences lacking the C-terminal amino acids phenylalanine or phenylalanine and aspartic acid. The terminal amino acid Y was converted to the 1-adamantylamide. The thus obtained truncated CCK sequences surprisingly show no agonist properties more but are able to inhibit cholecystokinin in concentrations of 10 ~ 7 to 10 "'mol / l. The novel compounds have been peptide-chemically in a conventional manner in stages od6r by either fragment condensation The protected peptide is then deprotected, acylated, and then sulfated with pyridinium acetyl sulfate, and finally purified by preparative HPLC on RP-18 isocratic with 25% acetonitrile. 0.05n ammonium acetate solution pH6.5
Die Erfindung wird anhand von Ausführungsb&ispielen näher erläutert. The invention will be explained in more detail by means of exemplary embodiments.
zum Hexapeptid verlängert. Erneutes Abspalten der Boc-Schutzgruppe und Acylierung mit Bernsteinsäureanhydrid führen zumextended to hexapeptide. Renegotiation of the Boc protecting group and acylation with succinic anhydride lead to
liefern Suc-TyrlSEl-Met-Gly-Trp-Met-Asp-i-Adamantylamid.provide Suc-TyrlSEl-Met-Gly-Trp-Met-Asp-i-adamantylamide.
0,01 mol H,P04/Acetonitril 28%-^2% (6 min)0.0 mol 1 H, P0 4 / acetonitrile 28% - ^ 2% (6 min)
kontraktionsauslösende Wirkung von CCK-8 kompetitiv. Bis zu einer Konzentration von 10"* Mol/l zeigte die Substanz keinerlei kontrahierende Eigenwitkung.Contraction-inducing effect of CCK-8 competitive. Up to a concentration of 10 "* mol / l, the substance showed no contracting Eigenwitkung.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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DD32106788A DD276482B5 (en) | 1988-10-25 | 1988-10-25 | Process for the preparation of new cholecystokinin sequences |
Applications Claiming Priority (1)
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DD32106788A DD276482B5 (en) | 1988-10-25 | 1988-10-25 | Process for the preparation of new cholecystokinin sequences |
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DD276482A1 true DD276482A1 (en) | 1990-02-28 |
DD276482B5 DD276482B5 (en) | 1996-08-08 |
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DD32106788A DD276482B5 (en) | 1988-10-25 | 1988-10-25 | Process for the preparation of new cholecystokinin sequences |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002070546A2 (en) * | 2001-03-01 | 2002-09-12 | University Of Ulster | Modified derivatives of cck-8 |
WO2002094873A2 (en) * | 2001-05-22 | 2002-11-28 | Bracco Imaging S.P.A. | Preparation of cholecystokinin agonists and antagonists, and their therapeutic and diagnostic use |
-
1988
- 1988-10-25 DD DD32106788A patent/DD276482B5/en not_active IP Right Cessation
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002070546A2 (en) * | 2001-03-01 | 2002-09-12 | University Of Ulster | Modified derivatives of cck-8 |
WO2002070546A3 (en) * | 2001-03-01 | 2002-12-05 | Univ Ulster | Modified derivatives of cck-8 |
AU2002238701B2 (en) * | 2001-03-01 | 2008-01-24 | Uutech Limited | Modified derivatives of CCK-8 |
WO2002094873A2 (en) * | 2001-05-22 | 2002-11-28 | Bracco Imaging S.P.A. | Preparation of cholecystokinin agonists and antagonists, and their therapeutic and diagnostic use |
WO2002094873A3 (en) * | 2001-05-22 | 2003-07-24 | Bracco Imaging Spa | Preparation of cholecystokinin agonists and antagonists, and their therapeutic and diagnostic use |
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Publication number | Publication date |
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DD276482B5 (en) | 1996-08-08 |
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