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Chemical Compound Review

U-50488H     2-(3,4-dichlorophenyl)-N- methyl-N-[(1R,2R)...

Synonyms: Lopac-D-8040, CHEMBL482811, AG-H-34991, D8040_SIGMA, CHEBI:584626, ...
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Disease relevance of Lopac-U-111

  • We found stimulation of OK cells with U50,488H significantly enhanced Na(+)/H(+) exchange, which was blocked by naloxone but not by pertussis toxin pretreatment, indicating it is mediated by KORs but independent of G(i)/G(o) proteins [1].
  • This antiserum was found to block U50,488H-mediated inhibition of 1) Staphylococcus aureus Cowen strain I-induced B and T lymphocyte proliferation, 2) PHA-induced T lymphocyte proliferation, and 3) S. aureus Cowen strain I-induced IgG production [2].
  • U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension [3].
  • CONCLUSIONS: The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease [3].
  • U50,488H-induced hypothermia was antagonized by the kappa antagonist nor-binaltorphimine but not by acute treatment with the irreversible kappa antagonist DIPPA [4].

Psychiatry related information on Lopac-U-111

  • In contrast, U50,488H (total dose = 10, 100 nmol) and dynorphin A(1-13) (total dose = 100 nmol) produced increased locomotor activity which was attenuated by pretreatment with naloxone and norbinaltorphimine, thus confirming the involvement of kappa-opioid receptors [5].
  • Nor-binaltorphimine (5.44 nmol/mouse i.c.v.) blocked the effect of U-50488H on CO-induced delayed amnesia [6].
  • The kappa-opioid receptor agonist, U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), dose dependently suppressed all measures of social behavior [7].
  • Dapiprazol prevents U50,488H-mediated suppression of preparatory components of drinking behavior in rats [8].
  • In contrast, morphine (5.6 mg/kg) and DTG (10 mg/kg), unlike U-50488H (10 mg/kg), significantly shifted the stimulus-generalization curve for cocaine to the left [9].

High impact information on Lopac-U-111

  • U50,488H at 3x10(-6) to 1x10(-4) mol/L increased cell viability concentration-dependently with an EC50 of 3.311x10(-6) mol/L [10].
  • To eliminate kappa-agonist actions within the supraoptic nucleus, we infused the kappa-agonist U50,488H (2.5 micrograms/hr at 0.5 micrograms/hr) into one supraoptic nucleus over 5 d to locally downregulate kappa-receptor function [11].
  • GEC1 expression slightly reduced U50,488H-promoted down-regulation, without affecting ligand binding affinity, receptor-G protein coupling, or U50,488H-induced desensitization and internalization [12].
  • Stable transfection of NHERF-1/EBP50 into OKH cells restored the stimulatory effect of U50,488H upon Na(+)/H(+) exchange [1].
  • In contrast to these results, a significant elevation in the expression of the chemokine receptor CCR2 was observed in U50,488H-treated cultures [13].

Chemical compound and disease context of Lopac-U-111


Biological context of Lopac-U-111

  • These data suggest that anti-kappa R-(33-52) 1) does not interact with the effector binding site of the receptor, but sterically interferes with U50,488H binding to the receptor; and/or 2) the antiserum interacts with a secondary binding site that is important for ligand binding, but may not be involved in signal transduction [2].
  • In addition, (-)U50,488H stimulation enhanced phosphorylation of the Flag-hkor, but not Flag-rkor [19].
  • Naloxone and the l-isomer levorphanol also protected the site from alkylation, whereas the d-isomer dextrorphan and the kappa-selective opioid U50,488H did not protect the site [20].
  • Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period [3].
  • Rats tolerant to U50,488H-induced diuresis were cross-tolerant to BW942C [21].

Anatomical context of Lopac-U-111

  • Studies conducted with anti-kappa R-(33-52) indicated that this antiserum effectively blocked U50,488H-mediated immunosuppression, but by itself did not enhance or suppress lymphocyte activation [2].
  • When stably expressed in CHO cells, Flag-r/hkor, but not Flag-h/rkor, was desensitized and phosphorylated after exposure to (-)U50,488H, indicating that the C-terminal domain plays a critical role in the differences [19].
  • These results indicate that U50,488H-induced down-regulation of the hkor involves GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms and receptors seem to be trafficked to lysosomes and proteasomes for degradation [22].
  • Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist [23].
  • Neuroprotective effect of MK-801 and U-50488H after contusive spinal cord injury [24].

Associations of Lopac-U-111 with other chemical compounds

  • Binding affinities of three peptide ligands (dynorphin A, alpha-neo-endorphin, and dynorphin B) and three nonpeptide ligands (norbinaltorphimine, U50,488H, and U69,593) for chimeras were determined and compared to those for mu and kappa opioid receptors [25].
  • The effects of intracerebroventricular administration of morphine, the selective mu-agonist DAMGO, the delta-agonist DPDPE, the kappa-preferring peptide dynorphin A(1-13) and the kappa-agonist U50,488H on locomotor behaviour in the guinea pig were investigated [5].
  • The present study examined the cross-tolerance profiles of associatively and nonassociatively morphine-tolerant rats with analgesia produced by morphine and fentanyl (mu-receptor agonists) and U50,488H (a kappa-receptor agonist) [26].
  • In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY [16].
  • Both U-54494A and U-50488H, in concentrations of 50 and 100 microM, respectively, reduced the magnitude of the orthodromically evoked CA1 population spikes after electrical stimulation of the stratum radiatum (100-200 microA, 70 microseconds, 0.1 Hz) [27].

Gene context of Lopac-U-111


Analytical, diagnostic and therapeutic context of Lopac-U-111

  • NO2Arg does not prevent tolerance to analgesia mediated by the kappa 1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H) or the kappa 3 agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of mu tolerance and dependence [31].
  • Rats were preconditioned by intravenous injection of 10 mg kg(-1) U50,488H, a selective kappa-opioid receptor agonist (U50,488H preconditioning) [32].
  • In other animals, microinjection of U-50488H into the same site elicited a similar water diuresis without a change in renal sympathetic nerve activity [33].
  • Intravenous infusion of the kappa opioid receptor agonists, ketocyclazocine (KC) and U-50488H, produced increases in urine flow rate [34].
  • In further studies, the antinatriuretic response produced by i.c.v. U-50488H was completely abolished in rats that had undergone chronic bilateral renal denervation, a technique used to remove the influence of the renal sympathetic nerves [35].


  1. kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. Huang, P., Steplock, D., Weinman, E.J., Hall, R.A., Ding, Z., Li, J., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2004) [Pubmed]
  2. Anti-human kappa opioid receptor antibodies: characterization of site-directed neutralizing antibodies specific for a peptide kappa R(33-52) derived from the predicted amino terminal region of the human kappa receptor. Buchner, R.R., Vogen, S.M., Fischer, W., Thoman, M.L., Sanderson, S.D., Morgan, E.L. J. Immunol. (1997) [Pubmed]
  3. Consequences of opiate agonist and antagonist in myocardial ischaemia suggest a role of endogenous opioid peptides in ischaemic heart disease. Lee, A.Y., Chen, Y.T., Kan, M.N., P'eng, F.K., Chai, C.Y., Kuo, J.S. Cardiovasc. Res. (1992) [Pubmed]
  4. Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice. Baker, A.K., Meert, T.F. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  5. Effects of intracerebroventricularly administered mu-, delta- and kappa-opioid agonists on locomotor activity of the guinea pig and the pharmacology of the locomotor response to U50,488H. Bot, G., Chahl, L.A., Brent, P.J., Johnston, P.A. Neuropharmacology (1992) [Pubmed]
  6. U-50488H, a selective kappa-opioid receptor agonist, improves carbon monoxide-induced delayed amnesia in mice. Hiramatsu, M., Hyodo, T., Kameyama, T. Eur. J. Pharmacol. (1996) [Pubmed]
  7. Mu- and kappa-opioid receptor-mediated opioid effects on social play in juvenile rats. Vanderschuren, L.J., Niesink, R.J., Spruijt, B.M., Van Ree, J.M. Eur. J. Pharmacol. (1995) [Pubmed]
  8. Dapiprazol prevents U50,488H-mediated suppression of preparatory components of drinking behavior in rats. Nencini, P., Graziani, M., Valeri, P. Pharmacol. Biochem. Behav. (1991) [Pubmed]
  9. Modulatory effects of morphine, U-50488H and 1,3-di-(2-tolyl)guanidine on cocaine-like discriminative stimulus in the rat using two-choice discrete-trial avoidance paradigm. Ukai, M., Mori, E., Kameyama, T. Methods and findings in experimental and clinical pharmacology. (1997) [Pubmed]
  10. Cardioprotection of preconditioning by metabolic inhibition in the rat ventricular myocyte. Involvement of kappa-opioid receptor. Wu, S., Li, H.Y., Wong, T.M. Circ. Res. (1999) [Pubmed]
  11. kappa-opioid regulation of neuronal activity in the rat supraoptic nucleus in vivo. Brown, C.H., Ludwig, M., Leng, G. J. Neurosci. (1998) [Pubmed]
  12. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. Chen, C., Li, J.G., Chen, Y., Huang, P., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2006) [Pubmed]
  13. Kappa-opioid regulation of thymocyte IL-7 receptor and C-C chemokine receptor 2 expression. Zhang, L., Rogers, T.J. J. Immunol. (2000) [Pubmed]
  14. Differential influence of D1 and D2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum. Capasso, A., Sorrentino, L. Br. J. Pharmacol. (1997) [Pubmed]
  15. Anti-arrhythmic effect of kappa-opioid receptor stimulation in the perfused rat heart: involvement of a cAMP-dependent pathway. Yu, X.C., Wang, H.X., Pei, J.M., Wong, T.M. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  16. Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats. Yu, X.C., Wang, H.X., Zhang, W.M., Wong, T.M. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  17. Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit. Feng, P., Rahim, R.T., Cowan, A., Liu-Chen, L.Y., Peng, X., Gaughan, J., Meissler, J.J., Adler, M.W., Eisenstein, T.K. Eur. J. Pharmacol. (2006) [Pubmed]
  18. Haloperidol and reduced haloperidol-induced exacerbation of the dystonia produced by the kappa opioid U50,488H in guinea-pigs is associated with inhibition of sigma binding sites: behavioural and autoradiographical studies. Brent, P.J. Brain Res. (1995) [Pubmed]
  19. Molecular basis of differences in (-)(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]benzeneacetamide-induced desensitization and phosphorylation between human and rat kappa-opioid receptors expressed in Chinese hamster ovary cells. Li, J., Li, J.G., Chen, C., Zhang, F., Liu-Chen, L.Y. Mol. Pharmacol. (2002) [Pubmed]
  20. Affinity labeling of mu opioid receptors by sulfhydryl alkylating derivatives of morphine and morphinone. Bidlack, J.M., Frey, D.K., Kaplan, R.A., Seyed-Mozaffari, A., Archer, S. Mol. Pharmacol. (1990) [Pubmed]
  21. Kappa opioid partial agonist activity of the enkephalin-like pentapeptide BW942C based on urination and in vitro studies in humans and animals. Vaupel, D.B., Cone, E.J., Johnson, R.E., Su, T.P. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  22. Mechanisms of agonist-induced down-regulation of the human kappa-opioid receptor: internalization is required for down-regulation. Li, J.G., Benovic, J.L., Liu-Chen, L.Y. Mol. Pharmacol. (2000) [Pubmed]
  23. Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning. Liu, J., Tsang, S., Wong, T.M. Endocrinology (2006) [Pubmed]
  24. Neuroprotective effect of MK-801 and U-50488H after contusive spinal cord injury. Gómez-Pinilla, F., Tram, H., Cotman, C.W., Nieto-Sampedro, M. Exp. Neurol. (1989) [Pubmed]
  25. Differential binding domains of peptide and non-peptide ligands in the cloned rat kappa opioid receptor. Xue, J.C., Chen, C., Zhu, J., Kunapuli, S., DeRiel, J.K., Yu, L., Liu-Chen, L.Y. J. Biol. Chem. (1994) [Pubmed]
  26. Cross-tolerance of associative and nonassociative morphine tolerance in the rat with mu- and kappa-specific opioids. Carter, B.L., Tiffany, S.T. Psychopharmacology (Berl.) (1996) [Pubmed]
  27. In vitro depressant effects of U-54494A, an anticonvulsant related to kappa opioids, in the hippocampus. Proietti, M.L., Scotti de Carolis, A., Frank, C., Zeng, Y.C., Sagratella, S. Neuropharmacology (1991) [Pubmed]
  28. Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate. Li, J.G., Chen, C., Liu-Chen, L.Y. J. Biol. Chem. (2002) [Pubmed]
  29. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. Wang, Y., Tang, K., Inan, S., Siebert, D., Holzgrabe, U., Lee, D.Y., Huang, P., Li, J.G., Cowan, A., Liu-Chen, L.Y. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  30. U50,488H-induced internalization of the human kappa opioid receptor involves a beta-arrestin- and dynamin-dependent mechanism. Kappa receptor internalization is not required for mitogen-activated protein kinase activation. Li, J.G., Luo, L.Y., Krupnick, J.G., Benovic, J.L., Liu-Chen, L.Y. J. Biol. Chem. (1999) [Pubmed]
  31. Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor. Kolesnikov, Y.A., Pick, C.G., Ciszewska, G., Pasternak, G.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  32. Failure to confer cardioprotection and to increase the expression of heat-shock protein 70 by preconditioning with a kappa-opioid receptor agonist during ischaemia and reperfusion in streptozotocin-induced diabetic rats. Qi, J.S., Kam, K.W., Chen, M., Wu, S., Wong, T.M. Diabetologia (2004) [Pubmed]
  33. Differential cardiovascular and renal responses produced by microinjection of the {kappa}-opioid U-50488H [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide) methane sulfonate] into subregions of the paraventricular nucleus. Gottlieb, H.B., Varner, K.J., Kenigs, V.A., Cabral, A.M., Kapusta, D.R. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  34. Role of renal nerves in excretory responses to administration of kappa agonists in conscious spontaneously hypertensive rats. Kapusta, D.R., Jones, S.Y., DiBona, G.F. J. Pharmacol. Exp. Ther. (1989) [Pubmed]
  35. Central kappa opioid receptor-evoked changes in renal function in conscious rats: participation of renal nerves. Kapusta, D.R., Obih, J.C. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
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