Dehydro Keto Methylene and Keto Methylene Analogues of Substance P. Synthesis and Biological Activity

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

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Abstract

The synthesis of dehydro keto methylene and keto methylene analogues of substance P using classical peptide synthesis is described. The following analogues were prepared: [pGlu6,Gly9ᛘ(COCH2)(Rs)Leu10]SP6-11 (4) and [pGlu6,-(Rs)Phe7ᛘ(COCH2)CRS)Phe8]SP6-11(8). The use of an improved deprotection scheme employing Meerwein's reagent (Et3 OBF4) made possible the syntheses of the novel dehydro keto methylene analogue [pGlu6,(Rs)Phe7ᛘ(COCH2)Δ(E)Phe8]SP6-11 (26) and the tetrapeptide analogue [pGlu6,(RS)Phe8ᛘ(COCH2)Gly9]SP6-9(-OMe) (23). Compound 4 was a weak agonist in provoking contractions of the guinea pig ileum. Compound 26 was a potent inhibitor of SP degradation in rat hypothalamus preparations, with an IC50 value of 1.8 μM.

Original languageEnglish
Pages (from-to)416-421
Number of pages6
JournalJournal of Medicinal Chemistry
Volume31
Issue number2
DOIs
StatePublished - 1 Feb 1988

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