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Chemical Compound Review

CHEMBL440765     N-methyl-2-phenyl-N- [(5S,7S,8S)-7...

Synonyms: SureCN726034, CHEBI:73357, AC1Q5HUW, KB-62197, DNC011829, ...
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Disease relevance of U69593

  • Pertussis toxin blocked U69593-mediated inhibition of DNA synthesis [1].
  • In the intestinal transit test U-69,593 at doses between 0.5 and 15 mg/kg i.p. only slightly slowed intestinal transit of a charcoal meal in rats with no dose-relation; it partly but significantly antagonized morphine-induced constipation [2].
  • The kappa-opioid agonist U-69593 affects intracellular calcium level in R1.1 mouse thymoma cell line [3].

Psychiatry related information on U69593

  • Following chronic treatment, dose-response profiles to QNP were obtained to assess the expression of sensitization; the effect of U69593 on locomotor activity in animals already sensitized to QNP was also assessed [4].
  • In vivo U-69,593 i.p. prolonged the reaction time of rats on a 55 degrees C hot-plate and the dose of naloxone required to antagonize this effect was 40 times the dose that antagonized morphine-induced antinociception, suggesting the involvement of the kappa-receptor [2].

High impact information on U69593

  • A subset of cells (29 of 83) were hyperpolarized by the kappa-opioid receptor agonist U69593 with an EC50 of 23 nM [5].
  • Dynorphin A(1-17) or U69593 inhibited mossy fiber synaptic responses in preparations in which the CA3 region was surgically isolated from the rest of the hippocampus [6].
  • Bath application of dynorphin A1-17 or U-69, 593 caused dual modulation of the peak amplitude of presumed monosynaptic AMPA receptor-mediated EPSPs, decreasing synaptic potentials at nanomolar concentrations in a majority of SG cells examined (dynorphin, 63%; U-69,593, 91%), and increasing EPSPs at micromolar concentrations [7].
  • U69593 enhanced KOR mRNA expression in both OA and RA FLS in a KOR antagonist-reversible manner [8].
  • KDN21 inhibited the activation of ERK1/2 by [D-Pen(2),D-Pen(5)]-enkephalin (delta(1)) and bremazocine (kappa(2)) but had no effect on the activation by deltorphin II (delta(2)) and (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide (U69593, kappa(1)) [9].

Chemical compound and disease context of U69593


Biological context of U69593

  • Most interestingly, the KOR agonist U69593 may exert an antiarthritic effect via up-regulation of KOR in OA and RA FLS [8].
  • Morphine (0.1 to 5 micrograms), but not U-69,593 (5 micrograms), injected into the PVN 10 minutes before oxytocin or apomorphine, was found to be able to prevent penile erection and yawning induced by the unilateral PVN microinjection of oxytocin (10 ng) or apomorphine (50 ng) [13].
  • Affinity of drugs and peptides for U-69,593-sensitive and -insensitive kappa opiate binding sites: the U-69,593-insensitive site appears to be the beta endorphin-specific epsilon receptor [14].
  • 4. Although naloxone benzoylhydrazone (NalBzoH), displaying high affinity towards the putative kappa3-opioid receptor, antagonized the inhibitory effects of dynorphin A1-13 and (-)-EKC on [3H]-dopamine and [14C]-ACh release as well as that of U69593 on [3H]-dopamine release, it displayed a low apparent affinity (IC50 about 100 nM) in each case [15].
  • Dynorphin A, U-69593 and delta-opioid agonists also reduced the excitatory postsynaptic potential, although they were less effective than DAMGO [16].

Anatomical context of U69593

  • Coinjection of kappa receptor cRNA with cRNA coding for a G protein-linked, inwardly rectifying, K+ channel (GIRK1, or KGA) resulted in oocytes that responded to the kappa agonist U-69593 by activating a large (1.0-1.5-microA) K+ current [17].
  • The contribution of individual opioid receptor subtypes in the spinal cord to analgesia at different developmental stages was investigated using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged postnatal day (P) 3, 10 and 21 [18].
  • Microinjections of the kappa opioid receptor agonist, U69593, attenuated the increase in tail-flick latency produced by activation of mu opioid receptors located within the ventrolateral periaqueductal gray [19].
  • Prodynorphin gene expression was still increased by U-69593 treatment in the hypothalamus and decreased in the caudate putamen [20].
  • Membranes isolated from COS-7 cells expressing the newt kappa receptor possessed a single, high-affinity (Kd = 1.5 nM) binding site for the kappa-selective agonist U69593 [21].

Associations of U69593 with other chemical compounds


Gene context of U69593

  • Data regarding the effects of U-69593 and nor-binaltorphimine in KO suggest that the kappa opioid receptor is up-regulated as a consequence of prodynorphin gene deletion and that this adaptation underlies the decrease in basal DA dynamics and cocaine-evoked DA levels observed in DYN KO mice [27].
  • The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model [28].
  • In the present study using whole-cell patch-clamp recordings, we demonstrate that a selective KOR agonist (U69593, 1 microm) directly inhibits a subset of principal and tertiary but not secondary neurons in the VTA [29].
  • Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area [30].
  • The TASK-like AEC was not modulated by PKA (forskolin, kappa opioid agonists U69593 and GR8696, somatostatin) but was inhibited by PKC activator phorbol-12-myristate-13 acetate (PMA) [31].

Analytical, diagnostic and therapeutic context of U69593

  • Also, microinjection of U69593 in the RVM did not increase tail-flick latency [32].
  • The proposed selective delta agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), and the selective kappa agonist, U-69,593, up to 2 and 15 mg/kg i.p., respectively, did not delay gastrointestinal transit [33].
  • METHODS: Four days after administration of Freund adjuvant into the hind paw of male Wistar rats, antinociceptive effects of intraplantar and subcutaneous injection of FE 200665 and FE 200666 were measured by paw pressure algesiometry and compared with the kappa-agonist U-69,593 [34].
  • Direct intrathecal injection of U69593 (0.3-10.0 micrograms/animal) into 9-16-day-old rats produced a dose-dependent, naloxone-reversible, antinociception when measured using the paw-pressure test [35].
  • Quantitative in situ hybridization histochemistry revealed that 0.32 mg/kg U69593 significantly decreased amphetamine-induced mRNA expression of all three neuropeptides; however, only the induction of preproenkephalin mRNA was decreased by 0.16 mg/kg [36].


  1. kappa-Opioid agonist modulation of [3H]thymidine incorporation into DNA: evidence for the involvement of pertussis toxin-sensitive G protein-coupled phosphoinositide turnover. Barg, J., Belcheva, M.M., Rowiński, J., Coscia, C.J. J. Neurochem. (1993) [Pubmed]
  2. Interaction of U-69,593 with mu-, alpha- and kappa-opioid binding sites and its analgesic and intestinal effects in rats. La Regina, A., Petrillo, P., Sbacchi, M., Tavani, A. Life Sci. (1988) [Pubmed]
  3. The kappa-opioid agonist U-69593 affects intracellular calcium level in R1.1 mouse thymoma cell line. Martin-Kleiner, I., Gabrilovac, J. Int. Immunopharmacol. (2002) [Pubmed]
  4. Kappa-opioid agonist U69593 potentiates locomotor sensitization to the D2/D3 agonist quinpirole: pre- and postsynaptic mechanisms. Perreault, M.L., Graham, D., Bisnaire, L., Simms, J., Hayton, S., Szechtman, H. Neuropsychopharmacology (2006) [Pubmed]
  5. kappa-Opioid receptors also increase potassium conductance. Grudt, T.J., Williams, J.T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Characterizing the site and mode of action of dynorphin at hippocampal mossy fiber synapses in the guinea pig. Castillo, P.E., Salin, P.A., Weisskopf, M.G., Nicoll, R.A. J. Neurosci. (1996) [Pubmed]
  7. kappa-opioid receptor agonists modulate excitatory transmission in substantia gelatinosa neurons of the rat spinal cord. Randić, M., Cheng, G., Kojic, L. J. Neurosci. (1995) [Pubmed]
  8. Kappa and delta opioid receptors are expressed but down-regulated in fibroblast-like synoviocytes of patients with rheumatoid arthritis and osteoarthritis. Shen, H., Aeschlimann, A., Reisch, N., Gay, R.E., Simmen, B.R., Michel, B.A., Gay, S., Sprott, H. Arthritis Rheum. (2005) [Pubmed]
  9. Interaction of bivalent ligand KDN21 with heterodimeric delta-kappa opioid receptors in human embryonic kidney 293 cells. Xie, Z., Bhushan, R.G., Daniels, D.J., Portoghese, P.S. Mol. Pharmacol. (2005) [Pubmed]
  10. Effects of kappa-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission. Collins, S.L., D'Addario, C., Izenwasser, S. Eur. J. Pharmacol. (2001) [Pubmed]
  11. Pertussis toxin reduces the day-night rhythm of nociception and mu and kappa opioid peptide-mediated antinociception in the snail, Cepaea nemoralis. Yu, N., Kavaliers, M. Peptides (1991) [Pubmed]
  12. Stimulation of mu and delta opioid receptors induces hyperalgesia while stimulation of kappa receptors induces antinociception in the hot plate test in the naked mole-rat (Heterocephalus glaber). Towett, P.K., Kanui, T.I., Juma, F.D. Brain Res. Bull. (2006) [Pubmed]
  13. Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain. Melis, M.R., Stancampiano, R., Gessa, G.L., Argiolas, A. Neuropsychopharmacology (1992) [Pubmed]
  14. Affinity of drugs and peptides for U-69,593-sensitive and -insensitive kappa opiate binding sites: the U-69,593-insensitive site appears to be the beta endorphin-specific epsilon receptor. Nock, B., Giordano, A.L., Cicero, T.J., O'Connor, L.H. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  15. Kappa1- and kappa2-opioid receptors mediating presynaptic inhibition of dopamine and acetylcholine release in rat neostriatum. Schoffelmeer, A.N., Hogenboom, F., Mulder, A.H. Br. J. Pharmacol. (1997) [Pubmed]
  16. Selective opioid agonists modulate afferent transmission in the rat nucleus tractus solitarius. Rhim, H., Glaum, S.R., Miller, R.J. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  17. Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes. Henry, D.J., Grandy, D.K., Lester, H.A., Davidson, N., Chavkin, C. Mol. Pharmacol. (1995) [Pubmed]
  18. Epidural opioid analgesia in infant rats I: mechanical and heat responses. Marsh, D., Dickenson, A., Hatch, D., Fitzgerald, M. Pain (1999) [Pubmed]
  19. Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function. Tershner, S.A., Mitchell, J.M., Fields, H.L. Pain (2000) [Pubmed]
  20. Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS. D'Addario, C., Di Benedetto, M., Izenwasser, S., Candeletti, S., Romualdi, P. Neuroscience (2007) [Pubmed]
  21. Cloning, heterologous expression and pharmacological characterization of a kappa opioid receptor from the brain of the rough-skinned newt, Taricha granulosa. Bradford, C.S., Walthers, E.A., Searcy, B.T., Moore, F.L. J. Mol. Endocrinol. (2005) [Pubmed]
  22. Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration. Schenk, S., Partridge, B., Shippenberg, T.S. Neuropsychopharmacology (2001) [Pubmed]
  23. Modulation of the neurotoxic effects of methamphetamine by the selective kappa-opioid receptor agonist U69593. El Daly, E., Chefer, V., Sandill, S., Shippenberg, T.S. J. Neurochem. (2000) [Pubmed]
  24. Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent. Seguin, L., Le Marouille-Girardon, S., Millan, M.J. Pain (1995) [Pubmed]
  25. Opioid receptor ligands in the neonatal rat spinal cord: binding and in vitro depression of the nociceptive responses. James, I.F., Bettaney, J., Perkins, M.N., Ketchum, S.B., Dray, A. Br. J. Pharmacol. (1990) [Pubmed]
  26. Nonopioid actions of the kappa-opioid receptor agonists, U 50488H and U 69593 on electrophysiologic properties of hippocampal CA3 neurons in vitro. Alzheimer, C., ten Bruggencate, G. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  27. Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Chefer, V.I., Shippenberg, T.S. Eur. J. Neurosci. (2006) [Pubmed]
  28. Variable modulation of opioid brain uptake by P-glycoprotein in mice. Dagenais, C., Graff, C.L., Pollack, G.M. Biochem. Pharmacol. (2004) [Pubmed]
  29. Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. Margolis, E.B., Hjelmstad, G.O., Bonci, A., Fields, H.L. J. Neurosci. (2003) [Pubmed]
  30. Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens. Fuentealba, J.A., Gysling, K., Magendzo, K., Andrés, M.E. J. Neurosci. Res. (2006) [Pubmed]
  31. Characterization and function of TWIK-related acid sensing K+ channels in a rat nociceptive cell. Cooper, B.Y., Johnson, R.D., Rau, K.K. Neuroscience (2004) [Pubmed]
  32. A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Ackley, M.A., Hurley, R.W., Virnich, D.E., Hammond, D.L. Pain (2001) [Pubmed]
  33. Role of peripheral mu, delta and kappa opioid receptors in opioid-induced inhibition of gastrointestinal transit in rats. Tavani, A., Petrillo, P., La Regina, A., Sbacchi, M. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  34. Analgesic and antiinflammatory effects of two novel kappa-opioid peptides. Binder, W., Machelska, H., Mousa, S., Schmitt, T., Rivière, P.J., Junien, J.L., Stein, C., Schäfer, M. Anesthesiology (2001) [Pubmed]
  35. Correlation of ontogeny with function of [3H]U69593 labelled kappa opioid binding sites in the rat spinal cord. Allerton, C.A., Smith, J.A., Hunter, J.C., Hill, R.G., Hughes, J. Brain Res. (1989) [Pubmed]
  36. Kappa opioid receptor stimulation decreases amphetamine-induced behavior and neuropeptide mRNA expression in the striatum. Tzaferis, J.A., McGinty, J.F. Brain Res. Mol. Brain Res. (2001) [Pubmed]
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