Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality.
Some of the biological effects demonstrated after administration of substance P (SP) in vivo can indirectly be attributed to the fragmentation of the undecapeptide to its N-terminal bioactive fragment SP(1-7). This heptapeptide (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is a major bioactive metabolite from SP that frequently exerts similar biological effects as the parent peptide but also, in several cases, completely opposite actions. Specific binding sites for the heptapeptide SP(1-7) that are separate from the SP preferred NK receptors have been identified. In this study we demonstrate that (a) the C-terminal part of the SP metabolite SP(1-7) is most important for binding as deduced from an Ala scan and that a replacement of Phe(7) for Ala is deleterious, (b) truncation of the N-terminal amino acid residues of SP(1-7) delivers peptides with retained binding activity, although with somewhat lower binding affinities than SP(1-7) and (c) a C-terminal amide group as a replacement for the terminal carboxy group of SP(1-7) and for all of the truncated ligands synthesized affords approximately 5-10-fold improvements of the binding affinities.
Fransson
Rebecca
R
Department of Medicinal Chemistry, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
Botros
Milad
M
Nyberg
Fred
F
Lindeberg
Gunnar
G
Sandström
Anja
A
Hallberg
Mathias
M
D000577:Amides / Q000737:chemistry; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D008566:Membranes / Q000378:metabolism; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D000577:Amides; D008024:Ligands; D010446:Peptide Fragments; D013373:Substance P; C036877:substance P (1-7)