TY - JOUR
T1 - New reduced peptide bond substance P agonists and antagonists
T2 - effects on smooth muscle contraction
AU - Zacharia, Susan
AU - Rossowski, Wojciech J.
AU - Ning-Yi, Jiang
AU - Hrbas, Pavel
AU - Ertan, Atilla
AU - Coy, David H.
N1 - Funding Information:
This research was supported in part by NIH Grant CA-45153. We would like to thank Dr. Michael B. Given, Department of Medicine. Tulane University School of Medicine for his valuable advice and help.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1991/10/22
Y1 - 1991/10/22
N2 - Following the recent discovery of a new substance P (SP) competitive pancreatic acini cell receptor antagonist containing a reduced peptide bond in place of the C-terminal peptide bond, a new series of full chain and short chain (heptapeptide and hexapeptide) substance P analogues have been prepared in which one of the C-terminal-region peptide bonds has been replaced by CH2NH or CH2O groups. They were compared for their ability to recognize NK1 and/or NK2 tachykinin receptor binding sites on guinea pig ileum and rat duodenum smooth muscle preparations, respectively. It was found that all full sequence SP pseudopeptides were agonists with much reduced bioactivity in both tested systems and, in addition, [Gly9 ψ CH2NH)Leu10,Leu11]SP was found to be a relatively selective agonist for NK1 binding sites. Substitution of leucine at position 11 of SP heptapseudopeptides with phenylalanine generated a pseudopeptide with weak agonist activity when Gln at position 5 was replaced by D-Phe, or antagonists when this residue was replaced by D-Nal or D-Cpa. [Leu9ψ(CH2NH)Leu11]SP-(6-11) with Gln at position 6 substituted by D-Phe was a relatively stronger antagonist in both assay systems. These results suggest that, as with several other peptide systems of late, manipulation of the peptide bonds in SP can produce receptor antagonists which in some cases approach the potency of the classic spantide series and, furthermore, that the approach might be used to induce NK receptor specificity in both agonist and antagonist analogs.
AB - Following the recent discovery of a new substance P (SP) competitive pancreatic acini cell receptor antagonist containing a reduced peptide bond in place of the C-terminal peptide bond, a new series of full chain and short chain (heptapeptide and hexapeptide) substance P analogues have been prepared in which one of the C-terminal-region peptide bonds has been replaced by CH2NH or CH2O groups. They were compared for their ability to recognize NK1 and/or NK2 tachykinin receptor binding sites on guinea pig ileum and rat duodenum smooth muscle preparations, respectively. It was found that all full sequence SP pseudopeptides were agonists with much reduced bioactivity in both tested systems and, in addition, [Gly9 ψ CH2NH)Leu10,Leu11]SP was found to be a relatively selective agonist for NK1 binding sites. Substitution of leucine at position 11 of SP heptapseudopeptides with phenylalanine generated a pseudopeptide with weak agonist activity when Gln at position 5 was replaced by D-Phe, or antagonists when this residue was replaced by D-Nal or D-Cpa. [Leu9ψ(CH2NH)Leu11]SP-(6-11) with Gln at position 6 substituted by D-Phe was a relatively stronger antagonist in both assay systems. These results suggest that, as with several other peptide systems of late, manipulation of the peptide bonds in SP can produce receptor antagonists which in some cases approach the potency of the classic spantide series and, furthermore, that the approach might be used to induce NK receptor specificity in both agonist and antagonist analogs.
KW - Duodenum (rat)
KW - Ileum (guinea-pig)
KW - NK receptors
KW - NK receptors
KW - Spantide
KW - Substance P
KW - Substance P analogues (hepta- and hexapseudopeptide)
UR - http://www.scopus.com/inward/record.url?scp=0025938850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025938850&partnerID=8YFLogxK
U2 - 10.1016/0014-2999(91)90890-3
DO - 10.1016/0014-2999(91)90890-3
M3 - Article
C2 - 1723044
AN - SCOPUS:0025938850
VL - 203
SP - 353
EP - 357
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 3
ER -