[D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C antagonizes neuromedin C-stimulated amylase release by acini isolated from the rat pancreas.
Two novel neuromedin C analogs [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C and [Leu9-psi-CH2NH-Leu10]neuromedin C, were synthesized by rapid solid phase methods and examined for their abilities to inhibit neuromedin C-stimulated amylase release by isolated rat pancreatic acini. Both analogs significantly inhibited maximally stimulated amylase release by neuromedin C in a dose-dependent manner with maximal inhibition seen at concentrations of 100 and 300 microM of [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C and [Leu9-psi-CH2NH-Leu10]neuromedin C, respectively. The IC50 (concentration required to half-maximally inhibit neuromedin C-stimulated amylase release) was 1.5 microM for [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C compared to a 13.4 microM IC50 for [Leu9-psi-CH2NH-Leu10]neuromedin C. The [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C analog produced a parallel rightward shift in the neuromedin C dose-response curve and Schild plots of the inhibition data gave a slope of 0.969 +/- 0.121 and a pA2 (apparent affinity for the acinar cell receptor in terms of neuromedin C receptor-stimulated amylase release) of 100 nM. While [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C significantly inhibited both neuromedin B- and gastrin releasing peptide-stimulated amylase release, the analog did not inhibit amylase release in response to either cholecystokinin octapeptide, vasoactive intestinal peptide, substance P, carbamylcholine, the Ca2+ ionophore A23187, forskolin, or 8-bromo-cyclic AMP. The results demonstrate that [D-Ala1, Leu9-psi-CH2NH-Leu10]neuromedin C is a potent, specific, and competitive antagonist for neuromedin C and peptides of the gastrin releasing peptide family and may serve as a useful molecule for exploring the physiological role of these peptides.
Pancreatico-Biliary Research Institute, Hospital of The Good Samaritan, Los Angeles, CA 90017.
J R
JR
Wisner
B G
BG
Xue
D H
DH
Coy
I G
IG
Renner
D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019886:Gastrin-Releasing Peptide; D008969:Molecular Sequence Data; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D010446:Peptide Fragments; D010455:Peptides; C065282:neuromedin C, Leu(9)-psi-(CH2NH)-Leu(10)-; C065281:neuromedin C, Ala(1)-Leu(9)-psi-(CH2NH)-Leu(10)-; D019886:Gastrin-Releasing Peptide; C040794:neuromedin C; D015287:Neurokinin B; C038393:neuromedin B; D000681:Amylases; D001839:Bombesin