Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2011-08, Vol.32 (8), p.1685-1699
• Main Authors: Uehara, Hirotsugu, González, Nieves, Sancho, Veronica, Mantey, Samuel A., Nuche-Berenguer, Bernardo, Pradhan, Tapas, Coy, David H., Jensen, Robert T.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; agonists; Animals; Biological and medical sciences; Bombesin; Bombesin receptor; bombesin receptors; BRS-3; Cell Line, Tumor; Fundamental and applied biological sciences. Psychology; Gastrin-releasing peptide; Gastrin-releasing peptide receptor; Humans; Ligands; Mice; Mice, Inbred BALB C; neoplasms; Neuromedin B; Neuromedin B receptor; Peptide mediated cytotoxicity; Peptides - pharmacology; pharmacology; phospholipase C; PRRT; Rats; Receptors, Bombesin - agonists; Receptors, Bombesin - metabolism; Satiety; Transfection; Tumor imaging; Vertebrates: endocrinology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2011.06.017

• Pharmacology of 24 natural occurring/synthetic bombesin related agonists is compared for rat and human receptor bearing tissues. • Binding affinities/potencies and efficacy of cell activation are determined for all peptides. • 12 peptides had high affinity/potency for hGRP receptors, 8 for hNMB receptors, 1 for hBRS-3 receptor. • There was no correlation between affinities for hGRP and rat GRP receptors, but there was with h- and rat NMB receptors. • Results show the human and rat peptide agonist pharmacophore for human and rat GRP receptors differ markedly. • Results also report a number of high affinity/potency agonists that may be useful for human studies. The mammalian bombesin (Bn)-receptor family [gastrin-releasing peptide-receptor (GRPR-receptor), neuromedin B-receptor (NMB receptor)], their natural ligands, GRP/NMB, as well as the related orphan receptor, BRS-3, are widely distributed, and frequently overexpressed by tumors. There is increased interest in agonists for this receptor family to explore their roles in physiological/pathophysiological processes, and for receptor-imaging/cytotoxicity in tumors. However, there is minimal data on human pharmacology of Bn receptor agonists and most results are based on nonhuman receptor studies, particular rodent-receptors, which with other receptors frequently differ from human-receptors. To address this issue we compared hNMB-/GRP-receptor affinities and potencies/efficacies of cell activation (assessing phospholipase C activity) for 24 putative Bn-agonists (12 natural, 12 synthetic) in four different cells with these receptors, containing native receptors or receptors expressed at physiological densities, and compared the results to native rat GRP-receptor containing cells (AR42J-cells) or rat NMB receptor cells (C6-glioblastoma cells). There were close correlations (r=0.92–99, p