Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P

Gerardo Byk, David Halle, Irena Zeltser, Gal Bitan, Zvi Selinger, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

The application of the concept of backbone cyclization to linear substance P (SP) analogs is presented. We describe the synthesis, characterization, and biological activity of a series of backbone-to-amino- terminus cyclic analogs of the C-terminal hexapeptide of SP. These analogs were designed on the basis of NMR data and molecular modeling of the selective NK-1 analog WS-septide (Ac[Arg6,Pro9]SP6-11). A series of peptides with the general formula: cyclo[-(CH2)(m)-NH-CO-(CH2)(n)-CO-Arg- Phe-Phe-N-]-CH2-CO-Leu-Met-NH2 (n = 2, 3, 6 and m = 2, 3, 4) was synthesized by solid phase methodology using Fmoc chemistry for the main chain and Boc chemistry for the building units [N(α)-(ω-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the ω-aminoalkyl chain. Cyclic and precyclic analogs were compared. They were purified by HPLC and characterized by mass spectroscopy and NMR. Biological activity and selectivity to the NK-1 neurokinin receptor were found to depend on cyclization and the ring size: The most active and selective analog had a ring of 20 atoms. This analog was found to have enhanced metabolic stability in various tissue preparation compared to WS-septide.

Original languageEnglish
Pages (from-to)3174-3178
Number of pages5
JournalJournal of Medicinal Chemistry
Volume39
Issue number16
DOIs
StatePublished - 2 Aug 1996

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