Ketomethylene Pseudopeptide Analogues of Substance P: Synthesis and Biological Activity

Ariel Ewenson; Ralph Laufer; Michael Chorev; Zvi Selinger; Chaim Gilon

doi:10.1021/jm00152a020

Ketomethylene Pseudopeptide Analogues of Substance P: Synthesis and Biological Activity

Ariel Ewenson, Ralph Laufer, Michael Chorev, Zvi Selinger, Chaim Gilon

Institute of Chemistry

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Two pseudopeptide analogues [Bz-(RS)PheV(COCH₂)Gly⁹]SP_8-11(I) and [pGlu⁶,(RS)Phe⁸ψ(COCH₂)Gly⁹]SP_6-11(II) of the substance P related C-terminal hexapeptide [pGlu⁶]SP_6-11were prepared as follows. The pseudodipeptidic unit H(RS)Pheψ(COCH₂)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The Nα-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu⁶]Sp_6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a K_iof 20 μM whereas analogue I was a weak inhibitor.

Original language	English
Pages (from-to)	295-299
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	29
Issue number	2
DOIs	https://doi.org/10.1021/jm00152a020
State	Published - 1986

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@article{e1374fc8037b49bdb4c3dd1fd40f682f,

title = "Ketomethylene Pseudopeptide Analogues of Substance P: Synthesis and Biological Activity",

abstract = "Two pseudopeptide analogues [Bz-(RS)PheV(COCH2)Gly9]SP8-11(I) and [pGlu6,(RS)Phe8ψ(COCH2)Gly9]SP6-11(II) of the substance P related C-terminal hexapeptide [pGlu6]SP6-11were prepared as follows. The pseudodipeptidic unit H(RS)Pheψ(COCH2)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The Nα-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu6]Sp6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a Kiof 20 μM whereas analogue I was a weak inhibitor.",

author = "Ariel Ewenson and Ralph Laufer and Michael Chorev and Zvi Selinger and Chaim Gilon",

year = "1986",

doi = "10.1021/jm00152a020",

language = "אנגלית",

volume = "29",

pages = "295--299",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

}

TY - JOUR

T1 - Ketomethylene Pseudopeptide Analogues of Substance P

T2 - Synthesis and Biological Activity

AU - Ewenson, Ariel

AU - Laufer, Ralph

AU - Chorev, Michael

AU - Selinger, Zvi

AU - Gilon, Chaim

PY - 1986

Y1 - 1986

N2 - Two pseudopeptide analogues [Bz-(RS)PheV(COCH2)Gly9]SP8-11(I) and [pGlu6,(RS)Phe8ψ(COCH2)Gly9]SP6-11(II) of the substance P related C-terminal hexapeptide [pGlu6]SP6-11were prepared as follows. The pseudodipeptidic unit H(RS)Pheψ(COCH2)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The Nα-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu6]Sp6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a Kiof 20 μM whereas analogue I was a weak inhibitor.

AB - Two pseudopeptide analogues [Bz-(RS)PheV(COCH2)Gly9]SP8-11(I) and [pGlu6,(RS)Phe8ψ(COCH2)Gly9]SP6-11(II) of the substance P related C-terminal hexapeptide [pGlu6]SP6-11were prepared as follows. The pseudodipeptidic unit H(RS)Pheψ(COCH2)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The Nα-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu6]Sp6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a Kiof 20 μM whereas analogue I was a weak inhibitor.

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DO - 10.1021/jm00152a020

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C2 - 2419559

AN - SCOPUS:0022638790

SN - 0022-2623

VL - 29

SP - 295

EP - 299

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Ketomethylene Pseudopeptide Analogues of Substance P: Synthesis and Biological Activity

Abstract

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