Discovery of a novel class of neuromedin B receptor antagonists, substituted somatostatin analogues

Mol Pharmacol. 1993 Oct;44(4):841-50.


Bombesin-related peptides have widespread activities in the central nervous system and peripheral tissues. Recent studies show two subtypes of receptors; a gastrin-releasing peptide (GRP) receptor subtype and a neuromedin B (NMB) receptor subtype exist. In contrast to the GRP receptor, no antagonists exist for the NMB receptor. In the present study we report that certain somatostatin (SS) octapeptide analogues function as selective NMB receptor antagonists. The most potent analogue, D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2, inhibited binding of 125I-[D-Tyr degree]NMB to NMB receptor-transfected 3T3 cells and C6 cells. This analogue had 100-fold lower affinity for GRP receptors. Structure-function studies were performed by synthesizing 18 structurally related SS octapeptide analogues; each of these analogues, but not native SS-14 or SS-28, also inhibited binding to NMB receptors. The stereochemistry at positions 1, 2, 7, and 8, the hydrophobicity and ring size of the substitution in positions 1, 3, and 4, and the basicity of the group in position 5 were all important in determining NMB receptor affinity. No SS octapeptide analogue increased [3H]inositol phosphates in NMB receptor-transfected cells; however, each analogue inhibited NMB-stimulated increases. The most potent analogue, D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2, caused a parallel rightward shift of the NMB dose-response curve, the Schild plot slope was not significantly different from unity, and the affinity was 230 nM. SS octapeptide analogues also interacted with SS receptors and mu-opioid receptors; however, there was no correlation between the affinities of the analogues for these receptors and their affinities for NMB receptors, demonstrating that these activities can be separated. The results demonstrate for the first time a class of antagonists with > 100-fold selectivity for NMB versus GRP receptors. Because the structural requirements for determining NMB, SS, and mu-opioid receptor activity differ, it is likely that highly selective, specific, high affinity NMB receptor antagonists can now be developed that will be useful in defining the role of NMB in various physiological processes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Analgesics / metabolism
  • Animals
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / metabolism
  • Guinea Pigs
  • Iodine Radioisotopes
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Neuropeptides / metabolism
  • Oligopeptides / pharmacology
  • Pancreas / metabolism
  • Pancreas / ultrastructure
  • Peptides, Cyclic / pharmacology*
  • Prosencephalon / metabolism
  • Prosencephalon / ultrastructure
  • Rats
  • Receptors, Bombesin / antagonists & inhibitors*
  • Receptors, Bombesin / metabolism
  • Receptors, Bombesin / physiology
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism
  • Somatostatin / analogs & derivatives*
  • Somatostatin / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transfection
  • Tritium
  • Tumor Cells, Cultured


  • Analgesics
  • Enkephalins
  • Iodine Radioisotopes
  • Neuropeptides
  • Oligopeptides
  • Peptides, Cyclic
  • Receptors, Bombesin
  • Receptors, Opioid, mu
  • Tritium
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Somatostatin