title: Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs.
abstract: 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<0.0001) between their affinities/potencies for the two hGRP- or hNMB-receptor cells. Twelve analogs had high affinities (≤ 1 nM) for hGRP receptor with 15 selective for it (greatest=GRP, NMC), eight had high affinity/potencies for hNMB receptors and four were selective for it. Only synthetic Bn analogs containing β-alanine(11) had high affinity for hBRS-3, but also had high affinities/potencies for all GRP-/hNMB-receptor cells. There was no correlation between affinities for human GRP receptors and rat GRP receptors (r=0.131, p=0.54), but hNMB receptor results correlated with rat NMB receptor (r=0.71, p<0.0001). These results elucidate the human and rat GRP-receptor pharmacophore for agonists differs markedly, whereas they do not for NMB receptors, therefore potential GRP-receptor agonists for human studies (such as Bn receptor-imaging/cytotoxicity) must be assessed on human Bn receptors. The current study provides affinities/potencies on a large number of potential agonists that might be useful for human studies.
authors: Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1804, USA.
authors: Hirotsugu
authors: H
authors: Uehara
authors: Nieves
authors: N
authors: González
authors: Veronica
authors: V
authors: Sancho
authors: Samuel A
authors: SA
authors: Mantey
authors: Bernardo
authors: B
authors: Nuche-Berenguer
authors: Tapas
authors: T
authors: Pradhan
authors: David H
authors: DH
authors: Coy
authors: Robert T
authors: RT
authors: Jensen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D018004:Receptors, Bombesin / Q000819:agonists* / Q000378:metabolism*; D014162:Transfection
chemical_list: D008024:Ligands; D010455:Peptides; D018004:Receptors, Bombesin