Synthesis and Biological Activity of NK-1 Selective, N-Backbone Cyclic Analogs of the C-Terminal Hexapeptide of Substance P
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 th...
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Published in | Journal of medicinal chemistry Vol. 39; no. 16; pp. 3174 - 3178 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
02.08.1996
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | Abstract published in Advance ACS Abstracts, July 1, 1996. istex:4E1E52DC4C6DCD116C4AE8448ED989C59CE2B036 ark:/67375/TPS-PKDB8285-G ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm960154i |