Structure-activity relationship of C-terminal hexa- and heptapeptide substance P antagonists as studied in the guinea-pig ileum.
The 14 C-terminal heptapeptide analogues and one hexapeptide analogue of substance P (SP) were synthesized on the basis of the SP antagonist [D-Pro2,D-Trp7,9]SP-(1-11). They were tested in the guinea-pig ileum preparation for spasmogenic and antagonistic activities. All analogues except two had antagonistic activity. Spasmogenic activity was observed in three heptapeptide SP antagonists: [Arg5,D-Trp7,D-pCl-Phe9]SP-(5-11), [Arg5,D-Trp7,9,p-Cl-Phe8]SP-(5-11) and [Arg5,D-Trp7,9,Nle11]SP-(5-11). However, this effect became greatly reduced upon successive applications in almost all ileum preparations. For antagonistic potency D-Trp turned out to be of greater importance in position 9 than in position 7 of the SP molecule. The presence of a free amino group at the N-terminal of the peptide was also of significant importance for antagonistic potency. Exchange of Met11 for Nle resulted in a considerable increase of antagonistic potency, while other substitutions in this position were ineffective or slightly reduced the antagonistic effect in the ileum preparation.
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D010446:Peptide Fragments; D013373:Substance P; C032132:substance P, prolyl(2)-tryptophan(7,9)-