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Chemical Compound Review

U-50,488H     2-(3,4-dichlorophenyl)-N- methyl-N-[(2R)-2...

Synonyms: CHEBI:399928, AC1L41SZ, 102636-38-4
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Disease relevance of U 50488

  • However, after exposure to U-50,488H (5 x 10(-7) M), naloxone (10(-6) M) produced a strong contracture if the agonist was washed out 1 min before the addition of the antagonist [1].
  • Previous studies have reported that large (microM) concentrations of kappa opioids, e.g. dynorphin and 3,4 dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzene-acetamide (U-50,488H), shorten the duration of the calcium component of the action potential of dorsal root ganglion neurons by decreasing a voltage-sensitive Ca2+ conductance [2].
  • The effects of the optical isomers and the racemic form of ketocyclazocine (KC) were compared with morphine and U-50,488H in the chronic spinal dog. l-KC and dl-KC produced depression of nociceptive reflexes, miosis, relaxation of the nictitating membrane and sedation, whereas d-KC lacked pharmacological activity [3].
  • Similarly, U-50,488H also produced a dose-dependent hypothermia in mice [4].
  • The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone [5].

Psychiatry related information on U 50488

  • No significant change in spontaneous locomotor activity was measured in the open field apparatus, suggesting that U-50,488H was devoid of sedative effects in the dose range tested (0.1-1000 micrograms/kg, IP) [6].
  • The effect of U-50,488H was consistent with de-satiation, so that the increase in feeding duration was in evidence from the start of the test period, while the temporal pattern of later satiation was preserved but lagged behind that of control animals [7].
  • Day-night rhythms in feeding behavior and response to the specific kappa opioid agonist U-50,488H (0.10-10. mg/kg) were measured in young (1-2 months), mature (8-12 months) and old (24-30 months) male CF-1 mice [8].
  • Effects of a selective kappa-opioid agonist, U-50,488H, on morphine dependence in rats [9].
  • Intra-VTA NBNI prevented U-50,488H-induced decreases in the mean number of ejaculations, intra-NAS NBNI prevented U-50,488H-induced increases in copulation latencies [10].

High impact information on U 50488

  • These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H [11].
  • Leucine enkephalin (10(-8) M) had no effect, whereas U-50,488H (10(-5) M) increased myofilament responsiveness to Ca2+ [12].
  • Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice [13].
  • The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U-50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats [14].
  • In single cardiac myocytes, acute stimulation of K opioid receptors with dynorphin B or with the selective agonist U-50,488H increased the level of cytosolic calcium [15].

Chemical compound and disease context of U 50488

  • The aim of the present study was to determine whether U-50,488H and U-62,066E, kappa-opioid receptor agonists cause a neuroprotective action against hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose (2-DG) uptake of hippocampal slices from U-50,488H-tolerant rats [16].
  • Effects of pertussis toxin on behavioural responses of guinea-pigs to centrally administered substance P, quinpirole, carbachol, U-50,488H, morphine and morphine withdrawal [17].
  • The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex [5].
  • Multiple injections of U-50,488H resulted in a slower gain in body weight which was not modified by treatment with NMMA [18].

Biological context of U 50488


Anatomical context of U 50488

  • Pretreatment of the membranes with kappa-selective compounds [ethylketocyclazocine (EKC), dynorphin (1-13), or U-50,488H] but not with [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO; mu specific ligand) or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DADLE; delta specific ligand) strongly protects the binding of the radioligands against NEM inactivation [23].
  • Using immunohistochemical staining of Fos, the present results indicate that acute treatment with either morphine or U-50,488H induces marked Fos immunoreactivity within the hypothalamus, including the medial parvicellular PVN and supraoptic and suprachiasmatic nuclei [24].
  • In addition, spinal U-50,488H produced changes in mechanical and thermal thresholds of the majority of superficial dorsal horn neurons [25].
  • Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding assay, we found that (-)U-50,488H was able to produce a nor-BNI-reversible increase in [35S]GTP gamma S binding to membranes of the mouse thalamus, which has a high level of kappa-opioid receptors [26].
  • One-third of the cells exhibited expansion of their receptive fields as defined using mechanical stimuli following a spinal kappa agonist (dynorphin or U-50,488H); receptive field expansions were of the same order as those observed immediately after a conditioning electrical stimulus applied to a peripheral nerve [25].

Associations of U 50488 with other chemical compounds


Gene context of U 50488

  • Changes in the properties of the kappa-opioid, 5-HT1 and 5-HT2 receptor binding sites in the cortical, striatal and spinal tissues of control and U-50,488H-tolerant mice were investigated [31].
  • 5-HT receptor antagonists (pindolol or ketanserin) were coadministered with U-50,488H to test for their effect on the development of tolerance to U-50,488H [31].
  • Mice deficient in the kappa-opioid receptor (KOR) gene have recently been developed by the technique of homologous recombination and shown to lack behavioural responses to the selective kappa1-receptor agonist U-50,488H [32].
  • Generalization of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists U-50,488H, but not TRK-820 in rats [33].
  • We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic kappa-agonist U-50,488H [34].

Analytical, diagnostic and therapeutic context of U 50488

  • We found similar dose-related analgesia when we tested the selective mu agonist [Try-D-Ala-Gly-NMe-Phe-Gly-ol] (0.01-1 microgram), the selective kappa receptor ligand U-50,488H (100-500 micrograms), the selective delta agonist [D-Pen2,5]-enkephalin (50-200 micrograms) and beta-endorphin (0.1-10 micrograms) [35].
  • Unilateral microinjections of specific mu (DAGO), delta (DPDPE) and kappa (U-50,488H) ligands into the substantia nigra pars reticulata of rats produced dose-dependent contralateral turning [36].
  • Rats were made tolerant dependent on U-50,488H by intraperitoneal injections of the drug (25 mg/kg) twice a day for 4 days [37].
  • No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H [38].
  • 6. In conclusion, U-50,488H at high concentration, had direct depressant actions on cardiac contractility, electrical excitability and the ECG [20].


  1. Withdrawal contractures of guinea-pig isolated ileum after acute activation of kappa-opioid receptors. Morrone, L.A., Romanelli, L., Amico, M.C., Valeri, P. Br. J. Pharmacol. (1993) [Pubmed]
  2. Dynorphin prolongs the action potential of mouse sensory ganglion neurons by decreasing a potassium conductance whereas another specific kappa opioid does so by increasing a calcium conductance. Shen, K.F., Crain, S.M. Neuropharmacology (1990) [Pubmed]
  3. Pharmacodynamic and pharmacokinetic actions of ketocyclazocine enantiomers in the dog: absence of sigma- or phencyclidine-like activity. Vaupel, D.B., Cone, E.J. J. Pharmacol. Exp. Ther. (1991) [Pubmed]
  4. Effect of thyrotropin releasing hormone on U-50,488H-induced pharmacological responses in mice. Bhargava, H.N., Thorat, S.N. Brain Res. (1993) [Pubmed]
  5. The use of specific opioid agonists and antagonists to delineate the vagally mediated antinociceptive and cardiovascular effects of intravenous morphine. Randich, A., Robertson, J.D., Willingham, T. Brain Res. (1993) [Pubmed]
  6. Kappa opioid agonists produce anxiolytic-like behavior on the elevated plus-maze. Privette, T.H., Terrian, D.M. Psychopharmacology (Berl.) (1995) [Pubmed]
  7. An observational analysis of the effect of the selective kappa opioid agonist, U-50,488H, on feeding and related behaviours in the rat. Jackson, A., Cooper, S.J. Psychopharmacology (Berl.) (1986) [Pubmed]
  8. The effects of aging on day-night rhythms of kappa opiate-mediated feeding in the mouse. Kavaliers, M., Teskey, G.C., Hirst, M. Psychopharmacology (Berl.) (1985) [Pubmed]
  9. Effects of a selective kappa-opioid agonist, U-50,488H, on morphine dependence in rats. Fukagawa, Y., Katz, J.L., Suzuki, T. Eur. J. Pharmacol. (1989) [Pubmed]
  10. The stimulation of central kappa opioid receptors decreases male sexual behavior and locomotor activity. Leyton, M., Stewart, J. Brain Res. (1992) [Pubmed]
  11. The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Contarino, A., Papaleo, F. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Ventura, C., Spurgeon, H., Lakatta, E.G., Guarnieri, C., Capogrossi, M.C. Circ. Res. (1992) [Pubmed]
  13. Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor. Matthes, H.W., Smadja, C., Valverde, O., Vonesch, J.L., Foutz, A.S., Boudinot, E., Denavit-Saubié, M., Severini, C., Negri, L., Roques, B.P., Maldonado, R., Kieffer, B.L. J. Neurosci. (1998) [Pubmed]
  14. A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems. Millan, M.J., Członkowski, A., Pilcher, C.W., Almeida, O.F., Millan, M.H., Colpaert, F.C., Herz, A. J. Neurosci. (1987) [Pubmed]
  15. Dynorphin gene expression and release in the myocardial cell. Ventura, C., Guarnieri, C., Vaona, I., Campana, G., Pintus, G., Spampinato, S. J. Biol. Chem. (1994) [Pubmed]
  16. Effects of naloxone, morphine and kappa-opioid receptor agonists on hypoxia/hypoglycemia-induced reduction of 2-deoxyglucose uptake in hippocampal slices from U-50,488H-tolerant rats. Shibata, S., Tominaga, K., Watanabe, S. Neurosci. Lett. (1994) [Pubmed]
  17. Effects of pertussis toxin on behavioural responses of guinea-pigs to centrally administered substance P, quinpirole, carbachol, U-50,488H, morphine and morphine withdrawal. Bot, G., Chahl, L.A. Eur. J. Pharmacol. (1993) [Pubmed]
  18. Nitric oxide synthase inhibition blocks tolerance to the analgesic action of kappa-opiate receptor agonist in the rat. Bhargava, H.N. Pharmacology (1994) [Pubmed]
  19. A subtype of kappa-opioid receptor mediates inhibition of high-affinity GTPase inherent in Gi1 in guinea pig cerebellar membranes. Ueda, H., Misawa, H., Fukushima, N., Katada, T., Ui, M., Satoh, M. J. Neurochem. (1996) [Pubmed]
  20. Cardiovascular actions of the kappa-agonist, U-50,488H, in the absence and presence of opioid receptor blockade. Pugsley, M.K., Penz, W.P., Walker, M.J., Wong, T.M. Br. J. Pharmacol. (1992) [Pubmed]
  21. Alteration of thermoregulatory set point with opioid agonists. Spencer, R.L., Hruby, V.J., Burks, T.F. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  22. Direct evidence for the up-regulation of spinal micro-opioid receptor function after repeated stimulation of kappa-opioid receptors in the mouse. Narita, M., Khotib, J., Mizoguchi, H., Suzuki, M., Ozaki, S., Yajima, Y., Tseng, L.F., Suzuki, T. Eur. J. Neurosci. (2003) [Pubmed]
  23. Selective protection of benzomorphan binding sites against inactivation by N-ethylmaleimide. Evidence for kappa-opioid receptors in frog brain. Zawilska, J., Lajtha, A., Borsodi, A. J. Neurochem. (1988) [Pubmed]
  24. Activation of c-fos expression in hypothalamic nuclei by mu- and kappa-receptor agonists: correlation with catecholaminergic activity in the hypothalamic paraventricular nucleus. Laorden, M.L., Castells, M.T., Martínez, M.D., Martínez, P.J., Milanés, M.V. Endocrinology (2000) [Pubmed]
  25. Effects of spinal kappa-opioid receptor agonists on the responsiveness of nociceptive superficial dorsal horn neurons. Hylden, J.L., Nahin, R.L., Traub, R.J., Dubner, R. Pain (1991) [Pubmed]
  26. Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception. Narita, M., Khotib, J., Suzuki, M., Ozaki, S., Yajima, Y., Suzuki, T. J. Neurochem. (2003) [Pubmed]
  27. Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse. Porreca, F., Mosberg, H.I., Hurst, R., Hruby, V.J., Burks, T.F. J. Pharmacol. Exp. Ther. (1984) [Pubmed]
  28. Sufentanil, morphine, met-enkephalin, and kappa-agonist (U-50,488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions. Chang, H.M., Berde, C.B., Holz, G.G., Steward, G.F., Kream, R.M. Anesthesiology (1989) [Pubmed]
  29. Kappa opioid analgesia is dependent on serotonergic mechanisms. Vonvoigtlander, P.F., Lewis, R.A., Neff, G.L. J. Pharmacol. Exp. Ther. (1984) [Pubmed]
  30. Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint. Nagasaka, H., Awad, H., Yaksh, T.L. Anesthesiology (1996) [Pubmed]
  31. Serotonergic involvement in the antinociceptive action of and the development of tolerance to the kappa-opioid receptor agonist, U-50, 488H. Ho, B.Y., Takemori, A.E. J. Pharmacol. Exp. Ther. (1989) [Pubmed]
  32. Quantitative autoradiography of mu-,delta- and kappa1 opioid receptors in kappa-opioid receptor knockout mice. Slowe, S.J., Simonin, F., Kieffer, B., Kitchen, I. Brain Res. (1999) [Pubmed]
  33. Generalization of NMDA-receptor antagonists to the discriminative stimulus effects of kappa-opioid receptor agonists U-50,488H, but not TRK-820 in rats. Mori, T., Nomura, M., Yoshizawa, K., Nagase, H., Sawaguchi, T., Narita, M., Suzuki, T. J. Pharmacol. Sci. (2006) [Pubmed]
  34. The kappa opioid receptor is associated with the perception of visceral pain. Black, D., Trevethick, M. Gut (1998) [Pubmed]
  35. Antinociceptive action of intracerebroventricularly administered dynorphin and other opioid peptides in the rat. Tiseo, P.J., Geller, E.B., Adler, M.W. J. Pharmacol. Exp. Ther. (1988) [Pubmed]
  36. Rotational behavior mediated by dopaminergic and nondopaminergic mechanisms after intranigral microinjection of specific mu, delta and kappa opioid agonists. Matsumoto, R.R., Brinsfield, K.H., Patrick, R.L., Walker, J.M. J. Pharmacol. Exp. Ther. (1988) [Pubmed]
  37. beta-Endorphin-like immunoreactivity in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and -abstinent rats. Bhargava, H.N., Matwyshyn, G.A., Rattan, A.K., Koo, K.L., Tejwani, G.A. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  38. Contralateral but not systemic administration of the kappa-opioid agonist U-50,488H induces anti-nociception in acute hindpaw inflammation in rats. Bileviciute-Ljungar, I., Spetea, M. Br. J. Pharmacol. (2001) [Pubmed]
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