title: Nonpeptide neuromedin B receptor antagonists inhibit the proliferation of C6 cells.
abstract: The ability of nonpeptide antagonists to interact with neuromedin B receptors on C6 cells was investigated. 2-[3-(2, 6-Diisopropyl-phenyl)-ureido]3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin- 2-yl-cyclohexylmethyl)-proprionate (PD165929), 3-(1H-indol-3-yl)-2-methyl-2-[3(4-nitro-phenyl)-ureido]-N-(1-pyridin- 2-yl-cyclohexylmethyl)-propionamide (PD168368) and 3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]- 2-m ethyl-2-[3-(4-nitro-phenyl)-ureido]-propionamide (PD176252) inhibited (125I-Tyr0)neuromedin B binding with IC50 values of 2000, 40 and 50 nM, respectively. Because neuromedin B is a G-protein coupled serpentine receptor, the effects of neuromedin B antagonists on second messenger production and proliferation were investigated. PD168368 inhibited the ability of 10 nM neuromedin B to cause elevation of cytosolic Ca2+, whereas it had no effect on basal cytosolic Ca2+. PD168368 inhibited the ability of 100 nM neuromedin B to cause elevation of c-fos mRNA. Also, PD168368 in a dose-dependent manner inhibited the ability of 100 nM neuromedin B to cause phosphorylation of focal adhesion kinase. Using a [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, the order of antagonist potency to inhibit C6 proliferation was PD168368=PD176252>PD165929. Also, 1 microM PD168368 and PD176252 significantly inhibited colony number using a proliferation assay in vitro. PD168368 significantly inhibited C6 xenograft growth in nude mice in vivo. These results indicate that PD168368 is a C6 cell neuromedin B receptor antagonist, which inhibits proliferation.
authors: Cell and Cancer Biology Department, Medicine Branch, National Cancer Institute, Bldg. KWC, Rm. 300, 9610 Medical Center Drive, Rockville, MD 20850, USA. moody@bprb.nci.nih.gov
authors: T W
authors: TW
authors: Moody
authors: R T
authors: RT
authors: Jensen
authors: L
authors: L
authors: Garcia
authors: J
authors: J
authors: Leyton
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C116775:PD 165929; C419604:PD 168368; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D015287:Neurokinin B; C038393:neuromedin B; C116774:PD 176252; D002118:Calcium