The pharmacology and molecular pharmacology of various gastrointestinal (GI) peptides are being investigated. One peptide receptor family was investigated during the year: those for bombesin- (Bn) related peptides. Bn-related peptides (GRP, NMB) interact primarily with three distinct receptors (GRP-R, NMB-R) and the orphan receptor, BRS-3 to mediate a number of effects in the GI tract and central nervous system (CNS). In recent studies we have addressed the ability of various described classes of agonists/antagonists of thee receptors to interact with human bombesin receptor members. We first synthesized 35 different synthetic putative peptide antagonists composed of 10 different chemical classes and examined their abilities to interact with human Bn receptors on both cell lines possessing a single subtype or Bn-R transfected cells containing receptor densities similar to seen on native cells. A number of classes of high affinity selective antagonists were identified which should be useful for in vivo studies. A similar study examined the ability of 24 natural occurring and synthetic Bn analogues to interact with these receptors as agonists and compared the results to the pharmacology in rat Bn expressing cells, which are commonly used in experimental studies. The results identified a number of selective high affinity agonists for the GRP and NMB receptor and showed that the rat GRP receptor pharmacophore differs substantially from that of the human and thus should not be used for extrapolating possible results to human receptors. Another study examined the molecular basis for selectivity of NMB for the NMB-R and of various synthetic analogues of Bn for the orphan receptor, BRS-3. The identification of these molecular determinants will provide information that may allow development of even more selective ligands for these receptors in the future

Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2011
Total Cost
$661,438
Indirect Cost
City
State
Country
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Moody, Terry W; Tashakkori, Nicole; Mantey, Samuel A et al. (2017) AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists. Front Endocrinol (Lausanne) 8:176
Ramos-Álvarez, Irene; Nakamura, Taichi; Mantey, Samuel A et al. (2016) Novel chiral-diazepines function as specific, selective receptor agonists with variable coupling and species variability in human, mouse and rat BRS-3 receptor cells. Peptides 75:8-17
Moreno, Paola; Ramos-Álvarez, Irene; Moody, Terry W et al. (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets 20:1055-73
Moody, Terry W; Nuche-Berenguer, Bernardo; Jensen, Robert T (2016) Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes 23:38-47
Nakamura, Taichi; Ramos-Álvarez, Irene; Iordanskaia, Tatiana et al. (2016) Molecular basis for high affinity and selectivity of peptide antagonist, Bantag-1, for the orphan BB3 receptor. Biochem Pharmacol 115:64-76
Moody, Terry W; Mantey, Samuel A; Moreno, Paola et al. (2015) ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth. Peptides 64:55-61
Ramos-Álvarez, Irene; Moreno, Paola; Mantey, Samuel A et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides 72:128-44
Moody, Terry W; Nuche-Berenguer, Bernardo; Moreno, Paola et al. (2015) CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells. J Mol Neurosci 56:663-72
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
Ramos-Álvarez, Irene; Mantey, Samuel A; Nakamura, Taichi et al. (2015) A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists. Peptides 66:26-42

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