Inhibition of the expression of ornithine decarboxylase by some kappa-opioidergic receptor ligands in difluoromethylornithine-resistant L1210 cells.
In difluoromethylornithine resistant L1210 cells stimulated to growth from quiescence, the selective kappa-opioidergic agonist trans-(+/-)-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneaceta mid e (U-50488H) caused a dose dependent inhibition of the induction of ODC activity, with a half-maximal effect at about 1 microM. U-50488H also provoked reduction of ODC mRNA level and increase of ODC turnover, as well as inhibition of cell growth. U-69593, another kappa-selective agonist, was only slightly effective. The action of U-50488H on ODC induction was not blocked by naloxone, beta-chlornaltrexamine or by the kappa-selective opioid antagonists Mr1452 and nor-binaltorphimine (nBNI). Actually Mr1452 and nBNI exerted some inhibitory effect. Furthermore, the separated enantiomers (+) and (-) of U-50488H were similarly effective. The (-)cis-(1S,2R)-U50488 stereoisomer, exhibiting low affinity for kappa and high affinity for sigma receptors and carbetapentane, another sigma ligand, also inhibited ODC induction, although less effectively than U-50488H. None of several other opioid ligands tested had significant effects on ODC induction. In conclusion, the inhibition of ODC expression by U-50488H does not involve classical, enantiospecific opioid receptors; rather, these results suggest the involvement of a distinct site of action linked to inhibition of lymphoid cell proliferation.
Flamigni
F
F
Dipartimento di Biochimica G. Moruzzi, Università di Bologna, Italy.
Stefanelli
C
C
Stanic
I
I
Muscari
C
C
Giaccari
A
A
Rossoni
C
C
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001483:Base Sequence; D044482:Benzeneacetamides; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004351:Drug Resistance; D000518:Eflornithine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007939:Leukemia L1210; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008969:Molecular Sequence Data; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000378:metabolism / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D044482:Benzeneacetamides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009955:Ornithine Decarboxylase; C045444:U 69593; D000518:Eflornithine