Synthesis and biological evaluation of dehydrophenylalanine containing substance P fragments

Abstract

Peptide fragments of Substance P corresponding to the C-terminal segments (6-11) and (4-11), which contain a putative β-turn, were synthesised using solution phase methodology. Analogs of Substance P were synthesised where the phenylalanine residue at position 8 was replaced by dehydrophenylalanine (ΔPhe) and the glycine residue in position 9 was replaced by alanine, valine, sarcosine (N-Me-Gly) and α-aminoisobutyric acid. In two of the analogs [8-ΔPhe, 9-Sar]-SP (4-11) (5) and [5,8-ΔPhe, 9-Aib]-SP (4-11) (7) glutamine residue at position 5 was also substituted by ΔPhe. These analogs were evaluated for their ability to cause smooth muscle contraction in guinea pig ileum preparation (in vitro) and for hypotensive activity (in vivo) in female rats anesthetized with urethane. In the hexapeptide series [8-ΔPhe]-SP (6-11) (1) and [8-ΔPhe, 9-Sar]-SP (6-11) (4) showed significant activity in both the assays. Octapeptide [5,8-ΔPhe, 9-Sar]-SP (4-11) (5) with ΔPhe residue in positions 5 and 8 and sarcosine in position 9 was found to be the most potent analog both in vitro and in vivo systems.