Abstract

I. Ability of peptides to function as bombesin receptor antagonists at the difference receptor subtypes. Two different receptors the gastrin-releasing peptide receptor (GRP-R) and neuromedin B receptor (NMB-R) mediate the action of bombesin- related peptides in mammals. We have developed 6 classes of GRP receptor antagonists but have only identified one class of NMB-R antagonists of low affinity. To attempt to find additional classes of NMB-R antagonists we have applied a number of the strategies applied to the GRP-receptor to NMB related peptides. The formation of COOH terminal truncated NMB peptides of different classes (amides, esters, alkyl amides); various pseudopeptides, D-amino substituted peptides or NH2 terminal truncated NMB analogues all did not result in any potent NMR-R antagonists: These results demonstrate that despite the fact GRP and NMB related peptides differ in only 2 amino acids and the receptors have 50% homology, the structure-function relationships and active comfirmations of the two receptors are markedly different. Novel strategies will have to be developed to produce NMB receptor antagonists.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK053100-08
Application #
2573665
Study Section
Special Emphasis Panel (DDB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1996
Total Cost
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Nuche-Berenguer, Bernardo; Jensen, R T (2015) Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms. Biochim Biophys Acta 1853:2371-82
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Berna, Marc J; Tapia, Jose A; Sancho, Veronica et al. (2009) Gastrointestinal growth factors and hormones have divergent effects on Akt activation. Cell Signal 21:622-38
Alves, Bryce N; Leong, Jeff; Tamang, David L et al. (2009) Pancreatic lipase-related protein 2 (PLRP2) induction by IL-4 in cytotoxic T lymphocytes (CTLs) and reevaluation of the negative effects of its gene ablation on cytotoxicity. J Leukoc Biol 86:701-12
Gonzalez, Nieves; Nakagawa, Tomoo; Mantey, Samuel A et al. (2009) Molecular basis for the selectivity of the mammalian bombesin peptide, neuromedin B, for its receptor. J Pharmacol Exp Ther 331:265-76
Seidita, G; Mirisola, M; D'Anna, R P et al. (2008) Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 147B:807-13
Igarashi, Hisato; Ito, Tetsuhide; Kuwano-Kojima, Mizuho et al. (2008) Involvement of VPAC1 and VPAC2 receptors in increasing local pancreatic blood flow in anesthetized rats. Pancreas 37:236-8
Moody, Terry W; Pradhan, Tapas; Mantey, Samuel A et al. (2008) Bombesin marine toxin conjugates inhibit the growth of lung cancer cells. Life Sci 82:855-61
Schumann, Michael; Nakagawa, Tomoo; Mantey, Samuel A et al. (2008) Function of non-visual arrestins in signaling and endocytosis of the gastrin-releasing peptide receptor (GRP receptor). Biochem Pharmacol 75:1170-85
Jensen, R T; Battey, J F; Spindel, E R et al. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev 60:1-42

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