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Chemical Compound Review

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

Synonyms: CHEBI:517861, AR-1H8391, LS-187068, LS-187676, AC1L2A3Y, ...
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Disease relevance of U 50488


Psychiatry related information on U 50488

  • Similarly, quinpirole appears to attenuate U-50,488-induced locomotor activity by stimulating postsynaptic D2-like receptors, since the D2/D3 agonist inhibited kappa opioid mediated behavior independent of endogenous DA levels [6].
  • Dependence to U-50,488, however, was qualitatively and pharmacologically distinct from morphine-dependence and is apparently a consequence of specific activity at kappa receptors [7].
  • We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms [8].
  • The hyperalgesic effect of U50,488 is not likely to be the result of antagonist action at a mu 2-isoreceptor; the general mu-antagonist, naloxone, and its less lipophilic quaternary analogue, both failed to produce a significant reduction in pain thresholds [9].
  • DPDPE, U50488 and SKF10047 had no discernible effect on maternal behavior [10].

High impact information on U 50488

  • Colonic distention reduced the 1-hour gastric emptying of solids by 40.1%, an effect blocked by fedotozine and U 50,488 (50 and 100 micrograms/kg); nor-binaltorphimine hydrochloride (1 mg/kg) antagonized the blocking effect of fedotozine [11].
  • COS-1 cells transfected with the coding region of this clone showed high-affinity binding to kappa opioid receptor-selective ligands such as dynorphin A and U-50,488 and also nonselective opioid ligands such as bremazocine, ethylketocyclazocine, and naloxone [12].
  • At 10-muM concentrations, the 2 structurally distinct GIRK channel blockers, SCH23390 and U50488H, caused complete inhibition of ADP-induced cPLA(2) phosphorylation and TXA(2) generation, without affecting the conversion of AA to TXA(2) or ADP-induced primary platelet aggregation in aspirin-treated platelets [13].
  • Astrocytes pretreated with small interfering RNA for arrestin3 were also unable to activate p38 in response to U50,488 treatment [14].
  • To study the in vivo effects induced by phosphorylation of KOR(S369), C57Bl/6 mice were administered single or repeated doses of the KOR agonist, U50,488, and isolated brain glycoprotein was probed with an antibody, KOR-P, that specifically recognized phosphoserine 369 KOR [15].

Chemical compound and disease context of U 50488


Biological context of U 50488

  • The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series [21].
  • Bilateral injections of U50488H elicited a relatively greater increase in mean arterial pressure than unilateral injections and a significant decrease in heart rate [22].
  • The effect of the kappa-agonist U50488 on the up-regulation of synapsin I was dose dependent and was blocked by the kappa-opiate antagonist norbinaltor-phimine [23].
  • Chronic (5 days) morphine (10-100 mg/kg), SNC-80 (10 mg/kg), or U50488H (10 mg/kg) was associated with the induction of tachyphylaxis to the acute effects [24].
  • DCC coupling of (+)- and (-)-7 with nitrophenylacetic acids followed by catalytic hydrogenation and treatment with thiophosgene afforded a series of six isomeric aryl isothiocyanate analogues of U50,488 [25].

Anatomical context of U 50488

  • By modifying [3H]NalBzoH binding conditions, we can selectively label either mu or kappa 3 receptors in calf striatal membranes or classical U50,488-sensitive kappa 1 receptors in guinea pig cerebellar membranes [26].
  • Finally, neither the kappa-receptor agonist U50488 nor its antagonist nor-binaltorphimine significantly affected the progressive motility of human spermatozoa [27].
  • The results also show that following chronic exposure of cultured cells to etorphine or U50488, there is a loss of kappa agonist inhibition of the cyclase [28].
  • The cardiovascular and neuroendocrine effects of a selective kappa-opiate receptor agonist (U50488H) microinjected into the nucleus tractus solitarii have been investigated in urethane-anaesthetized rats [22].
  • In mixed glial cell aggregates, U50488 increased thymidine incorporation into DNA 3.1-fold, and this stimulation was reversed by the opioid antagonist naltrexone [29].

Associations of U 50488 with other chemical compounds

  • The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils [30].
  • DAMGO at concentrations between 1 nM and 1 microM competed with [3H]diprenorphine for the solubilized binding sites; in contrast, [D-Pen2, D-Pen5]-enkephalin, a delta-selective opioid agonist, and U50488H, a kappa-selective opioid agonist, failed to compete with [3H]diprenorphine for the solubilized binding sites at concentrations of < 1 microM [31].
  • 3. The respiratory burst frequency and amplitude in vitro were unaffected by the addition of the delta-opioid receptor agonist DPDPE ([D-pen2,5]-enkephalin) and the kappa-opioid receptor agonist U50488 (trans-[+]-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl) benzene-acetamide) or the opioid receptor antagonist naloxone [32].
  • We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance [33].
  • Acute treatments with high doses of sufentanil and morphine (mu-agonists), SNC-80 (delta-agonist), and U50488H (kappa-agonist) induced significant decreases (30-60%) in FADD immunodensity in the cerebral cortex, through specific opioid receptor mechanisms (effects antagonized by naloxone, naltrindole, or nor-binaltorphimine) [24].

Gene context of U 50488

  • Treatment of astrocytes with U50,488 inhibited Tat-induced MCP-1 production in a concentration-dependent manner [34].
  • It is well known that activation of the cloned kappa-opioid receptor by nanomolar concentrations of U50488H (trans-(+/-)-3, 4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl-benzeneacetamide) , a selective kappa-opioid receptor agonist, leads to the opening of GIRK1 channels [35].
  • Similarly, improgan analgesia was equivalent in all three genotypes of KOR-1 mutant mice, whereas kappa-mediated analgesia (U50,488) and kappa opioid (3H-U69,593) binding were abolished in the homozygous (-/-) mice [36].
  • The results indicate that the calcium currents elicited in dorsal root ganglion neurons can be depressed by U50488H, an effect readily reversed by the kappa-opioid receptor antagonist Nor-BNI or by the antiopioid peptide CCK-8 [37].
  • In these MOR-knockout mice, the analgesic effects of morphine, its major metabolites, morphine-6-glucuronide (M-6-G) and morphine-6-ethereal sulfate (M-6-S), and endomorphin-2, as well as morphine-induced lethality, were drastically reduced, whereas the effects of DPDPE and U50488 remained unchanged [38].

Analytical, diagnostic and therapeutic context of U 50488

  • Western blot analysis using KOR-P antibody showed that labeling intensity increased after either single or repeated treatment of mice with U50,488 by 59 +/- 22% and 101 +/- 29%, respectively [15].
  • Greater improvement in neurological function was seen after treatment with dynorphin (P < .05) than with U-50,488 (P < .6) or E3800 (P < .7) [39].
  • Acute intravenous injection of the kappa-agonist U50488H or the mu-agonist morphine (1-5 mg kg-1) reduced the firing rate of identified oxytocin neurones by 97.7 +/- 4.8% (n = 6) and 94.1 +/- 4.1% (n = 7), respectively [40].
  • In these rats, naloxone produced a large, sustained, fluctuating increase in intramammary pressure indicating morphine-withdrawal excitation of oxytocin secretion; I.V. U50,488 diminished this response, confirmed by radioimmunoassay, demonstrating the independence of mu- and kappa-receptors regulating oxytocin secretion [41].
  • However, the 10- and 30-micrograms doses could reverse completely the analgesia produced by U50488H [42].


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  4. Effects of pharmacological preconditioning with U50488H on calcium homeostasis in rat ventricular myocytes subjected to metabolic inhibition and anoxia. Ho, J.C., Wu, S., Kam, K.W., Sham, J.S., Wong, T.M. Br. J. Pharmacol. (2002) [Pubmed]
  5. The kappa agonists PD117302 and U50488 produce a biphasic effect on 24 hour food intake in the rat. Hewson, G., Hill, R.G., Hughes, J., Leighton, G.E., Turner, W.D. Neuropharmacology (1987) [Pubmed]
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  8. The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence. Tao, P.L., Liu, W.C., Tsuei, Y.S., Cheng, C.Y. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
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  10. Opioid receptor subtype involvement in maternal behavior in lactating rats. Mann, P.E., Kinsley, C.H., Bridges, R.S. Neuroendocrinology (1991) [Pubmed]
  11. The kappa agonist fedotozine modulates colonic distention-induced inhibition of gastric motility and emptying in dogs. Gué, M., Junien, J.L., Buéno, L. Gastroenterology (1994) [Pubmed]
  12. Cloning and pharmacological characterization of a rat kappa opioid receptor. Meng, F., Xie, G.X., Thompson, R.C., Mansour, A., Goldstein, A., Watson, S.J., Akil, H. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  13. G-protein-gated inwardly rectifying potassium channels regulate ADP-induced cPLA2 activity in platelets through Src family kinases. Shankar, H., Kahner, B.N., Prabhakar, J., Lakhani, P., Kim, S., Kunapuli, S.P. Blood (2006) [Pubmed]
  14. Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. Bruchas, M.R., Macey, T.A., Lowe, J.D., Chavkin, C. J. Biol. Chem. (2006) [Pubmed]
  15. Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance. McLaughlin, J.P., Myers, L.C., Zarek, P.E., Caron, M.G., Lefkowitz, R.J., Czyzyk, T.A., Pintar, J.E., Chavkin, C. J. Biol. Chem. (2004) [Pubmed]
  16. Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine. Vanderschuren, L.J., Schoffelmeer, A.N., Wardeh, G., De Vries, T.J. Psychopharmacology (Berl.) (2000) [Pubmed]
  17. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. Di Chiara, G., Imperato, A. J. Pharmacol. Exp. Ther. (1988) [Pubmed]
  18. Cyclic AMP regulates the calcium transients released from IP(3)-sensitive stores by activation of rat kappa-opioid receptors expressed in CHO cells. Ikeda, M., Nelson, C.S., Shinagawa, H., Shinoe, T., Sugiyama, T., Allen, C.N., Grandy, D.K., Yoshioka, T. Cell Calcium (2001) [Pubmed]
  19. Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes. Peterson, P.K., Gekker, G., Lokensgard, J.R., Bidlack, J.M., Chang, A.C., Fang, X., Portoghese, P.S. Biochem. Pharmacol. (2001) [Pubmed]
  20. Kappa-opioid receptor agonist inhibition of HIV-1 envelope glycoprotein-mediated membrane fusion and CXCR4 expression on CD4(+) lymphocytes. Lokensgard, J.R., Gekker, G., Peterson, P.K. Biochem. Pharmacol. (2002) [Pubmed]
  21. Conformational analysis and automated receptor docking of selective arylacetamide-based kappa-opioid agonists. Subramanian, G., Paterlini, M.G., Larson, D.L., Portoghese, P.S., Ferguson, D.M. J. Med. Chem. (1998) [Pubmed]
  22. Selective cardiovascular and neuroendocrine effects of a kappa-opioid agonist in the nucleus tractus solitarii of rats. Carter, D.A., Lightman, S.L. J. Physiol. (Lond.) (1985) [Pubmed]
  23. Long-term opiate exposure leads to increase in synapsin I in rat spinal cord-dorsal root ganglion cocultures. Nah, S.Y., Saya, D., Vogel, Z. J. Neurochem. (1993) [Pubmed]
  24. Effects of opiate drugs on Fas-associated protein with death domain (FADD) and effector caspases in the rat brain: regulation by the ERK1/2 MAP kinase pathway. García-Fuster, M.J., Miralles, A., García-Sevilla, J.A. Neuropsychopharmacology (2007) [Pubmed]
  25. Probes for narcotic receptor mediated phenomena. 17. Synthesis and evaluation of a series of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet amide (U50,488) related isothiocyanate derivatives as opioid receptor affinity ligands. de Costa, B.R., Rothman, R.B., Bykov, V., Band, L., Pert, A., Jacobson, A.E., Rice, K.C. J. Med. Chem. (1990) [Pubmed]
  26. Affinity labeling of mu and kappa receptors with naloxone benzoylhydrazone. Standifer, K.M., Murthy, L.R., Kinouchi, K., Steele, L., Pasternak, G.W. Mol. Pharmacol. (1991) [Pubmed]
  27. Expression and Localization of {delta}-, {kappa}-, and {micro}-Opioid Receptors in Human Spermatozoa and Implications for Sperm Motility. Agirregoitia, E., Valdivia, A., Carracedo, A., Casis, L., Gil, J., Subiran, N., Ochoa, C., Irazusta, J. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  28. Kappa-opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord. Attali, B., Saya, D., Vogel, Z. J. Neurochem. (1989) [Pubmed]
  29. 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]
  30. Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils. Hall, E.D., Pazara, K.E. Stroke (1988) [Pubmed]
  31. Solubilization of high-affinity, guanine nucleotide-sensitive mu-opioid receptors from rat brain membranes. Weems, H.B., Chalecka-Franaszek, E., Côté, T.E. J. Neurochem. (1996) [Pubmed]
  32. Opioid depression of respiration in neonatal rats. Greer, J.J., Carter, J.E., al-Zubaidy, Z. J. Physiol. (Lond.) (1995) [Pubmed]
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  34. U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. Sheng, W.S., Hu, S., Lokensgard, J.R., Peterson, P.K. Biochem. Pharmacol. (2003) [Pubmed]
  35. The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands. Ulens, C., Daenens, P., Tytgat, J. Eur. J. Pharmacol. (1999) [Pubmed]
  36. Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice. Hough, L.B., Nalwalk, J.W., Chen, Y., Schuller, A., Zhu, Y., Zhang, J., Menge, W.M., Leurs, R., Timmerman, H., Pintar, J.E. Brain Res. (2000) [Pubmed]
  37. Cholecystokinin octapeptide reverses the kappa-opioid-receptor-mediated depression of calcium current in rat dorsal root ganglion neurons. Xu, T., Liu, N.J., Li, C.Q., Shangguan, Y., Yu, Y.X., Kang, H.G., Han, J.S. Brain Res. (1996) [Pubmed]
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  42. Role of mu and kappa opioid receptors in conditional fear-induced analgesia: the antagonistic actions of nor-binaltorphimine and the cyclic somatostatin octapeptide, Cys2Tyr3Orn5Pen7-amide. Fanselow, M.S., Calcagnetti, D.J., Helmstetter, F.J. J. Pharmacol. Exp. Ther. (1989) [Pubmed]
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