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Chemical Compound Review

CHEMBL289498     1-(2-methyl-3-oxo-6-phenyl- 2,5...

Synonyms: SureCN1650330, CHEBI:105371, AC1L2XQK, L-365260, L000333, ...
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Disease relevance of L-365260

  • Our data illustrate a differential and limited effect of L-365,260 on opioid antinociception in carrageenin-injected rats, depending on the dose of morphine, the phase of inflammation and the intensity of hyperalgesia [1].
  • The ability of pretreatment by the selective cholecystokinin-B (CCK(B)) receptor antagonist L-365,260 (0.2 mg/kg s.c.) to prevent the development of tolerance to the antinociceptive action of morphine was evaluated by a well-established rat model of unilateral peripheral mononeuropathy [2].
  • We conclude that the gastrin/CCK-B receptor antagonist L-365,260, at doses supramaximal for the inhibition of pentagastrin-stimulated secretory responses in vivo, inhibits gastrointestinal damage in models of peptic ulcer disease by an antisecretory mechanism of action [3].
  • To investigate the safety and tolerability of L-365,260 in human subjects taking morphine for intractable pain [4].
  • In the gastric fistula cat, i.v. administration of YM022 produced a similar inhibitory effect with an ID50 of 0.02 mumol/kg in comparison to 1.6 and 2.5 mumol/kg for CI-988 and L-365,260, respectively [5].

Psychiatry related information on L-365260


High impact information on L-365260


Chemical compound and disease context of L-365260


Biological context of L-365260

  • Contraction induced by 10 nmol/L CCK was inhibited as follows: L 365,260 half maximal inhibition (IC50) = 1 nmol/L greater than L 364,718 (IC50 = 90 nmol/L) greater than proglumide (IC50 = 1 mumol/L) [16].
  • The neurogenic vasodilatation induced by CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal NO synthase (nNOS) inhibitors, but was independent of the endothelium [17].
  • In the present study, we examined whether amino acid substitutions within the CCK-BR pocket altered the affinities and/or functional activities of L-365,260 (the prototypical nonpeptide CCK-BR antagonist) and two structural derivatives, YM022 (a higher affinity antagonist) and L-740,093S (a partial agonist) [18].
  • 2. Competition curves obtained for L-365,260 in the mouse cortex assay were not different from rectangular hyperbolae (slope = 1.01 +/- 0.02) implying the presence of a single population of binding sites (pKI = 8.41 +/- 0.01; data from 47 experiments, slope constrained to unity) [19].
  • We showed that L-365,260 acted beyond receptor activation and production of intracellular second messengers and that it had no action on the H+/K+ -ATPase [20].

Anatomical context of L-365260

  • L-364,718 (10 ng), L-365,260 (10 ng), and CI-988 (20 ng or 2 micrograms), microinjected into the medial posterior nucleus accumbens, anterior nucleus accumbens, or ventral tegmental area, had no effect on baseline exploratory locomotion or on dopamine-induced changes in exploratory locomotion [21].
  • The CCK-B antagonists CI-988 (20 ng) and L-365,260 (10 ng) blocked CCK potentiation of dopamine-induced hypolocomotion in the ventral tegmental area [21].
  • Receptor antagonists that inhibit the biological effects and binding of peptides to the CCK-A (L-364,718 (L18)) and CCK-B (L-365,260 (L60)) receptors were ineffective toward inhibiting the binding and proliferative effects of gastrin on Swiss 3T3 cells [22].
  • The specific gastrin antagonist L-365,260 inhibited the (partial) agonist activity of PD-136,450 in the stomach and the specific CCK-A receptor antagonist L-364,718 inhibited the agonist activity of PD-136,450 in the pancreas [23].
  • Plasma L-365,260 concentrations (all doses combined) and the inhibition of gastric acid output were correlated with a correlation coefficient of r = 0.45 (p < 0.05) [24].

Associations of L-365260 with other chemical compounds


Gene context of L-365260

  • The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200 [30].
  • Unexpectedly, the CCK-B receptor antagonist, L-365,260, enhanced the response to CCK-8, an effect diametrically opposite to that produced by CCK-A antagonists [31].
  • Both these stimulating effects were abolished by L-365,260 or GV150013 (CCK-2 receptor antagonists), but were unaffected by SC-560 (COX-1 inhibitor) [32].
  • A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260 [33].
  • Subcutaneously administered selective CCK-A receptor antagonist, L-364,718 (1 mg/kg), reversed the inhibitory effect of centrally as well as peripherally administered CCK-8, but the selective CCK-B receptor antagonist, L-365,260 (1 mg/kg), did not [34].

Analytical, diagnostic and therapeutic context of L-365260


  1. The enhancement of morphine antinociception by a CCKB receptor antagonist in the rat depends on the phase of inflammation and the intensity of carrageenin-induced hyperalgesia. Perrot, S., Idänpään-Heikkilä, J.J., Guilbaud, G., Kayser, V. Pain (1998) [Pubmed]
  2. Prevention of tolerance to the antinociceptive effects of systemic morphine by a selective cholecystokinin-B receptor antagonist in a rat model of peripheral neuropathy. Idänpään-Heikkilä, J.J., Guilbaud, G., Kayser, V. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  3. The gastrin/cholecystokinin-B receptor antagonist L-365,260 reduces basal acid secretion and prevents gastrointestinal damage induced by aspirin, ethanol and cysteamine in the rat. Pendley, C.E., Fitzpatrick, L.R., Ewing, R.W., Molino, B.F., Martin, G.E. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  4. A phase 1 study of the cholecystokinin (CCK) B antagonist L-365,260 in human subjects taking morphine for intractable non-cancer pain. McCleane, G.J. Neurosci. Lett. (2002) [Pubmed]
  5. YM022, a highly potent and selective CCKB antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands. Attoub, S., Moizo, L., Laigneau, J.P., Alchepo, B., Lewin, M.J., Bado, A. Fundamental & clinical pharmacology. (1998) [Pubmed]
  6. The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder. Bradwejn, J., Koszycki, D., Couëtoux du Tertre, A., van Megen, H., den Boer, J., Westenberg, H. Arch. Gen. Psychiatry (1994) [Pubmed]
  7. Differential involvement of CCK-A and CCK-B receptors in the regulation of locomotor activity in the mouse. Vasar, E., Harro, J., Lang, A., Pôld, A., Soosaar, A. Psychopharmacology (Berl.) (1991) [Pubmed]
  8. Characterization of the role of endogenous cholecystokinin on the activity of the paraventricular nucleus of the hypothalamus in rats. Cano, V., Ezquerra, L., Ramos, M.P., Ruiz-Gayo, M. Br. J. Pharmacol. (2003) [Pubmed]
  9. The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat. Dourish, C.T., O'Neill, M.F., Coughlan, J., Kitchener, S.J., Hawley, D., Iversen, S.D. Eur. J. Pharmacol. (1990) [Pubmed]
  10. Postponement of satiety by blockade of brain cholecystokinin (CCK-B) receptors. Dourish, C.T., Rycroft, W., Iversen, S.D. Science (1989) [Pubmed]
  11. A locus and mechanism of action for associative morphine tolerance. Mitchell, J.M., Basbaum, A.I., Fields, H.L. Nat. Neurosci. (2000) [Pubmed]
  12. Influence of gastrin on human astrocytic tumor cell proliferation. Camby, I., Salmon, I., Danguy, A., Pasteels, J.L., Brotchi, J., Martinez, J., Kiss, R. J. Natl. Cancer Inst. (1996) [Pubmed]
  13. Cholecystokinin modulates both the development and the expression of behavioral sensitization to amphetamine in the rat. Wunderlich, G.R., DeSousa, N.J., Vaccarino, F.J. Psychopharmacology (Berl.) (2000) [Pubmed]
  14. Selective blockade of cholecystokinin type B receptors with L-365,260 does not impair gallbladder contraction in normal humans. Grasing, K., Freedholm, D., Murphy, M.G., Swigar, M., Russer, T., Nosher, J., Lin, J., Frame, V., Clarke, L., Seibold, J.R. Am. J. Gastroenterol. (1996) [Pubmed]
  15. Cholecystokinin B receptor antagonists enhance the locomotor response to the N-methyl-D-aspartate antagonists phencyclidine and dizocilpine maleate. Blacker, D., Broberger, C., Ogren, S.O., Hökfelt, T. Neuroscience (1997) [Pubmed]
  16. Cholecystokinin and gastrin induce cell contraction in pig ileum by interacting with different receptor subtypes. Botella, A., Delvaux, M., Berry, P., Frexinos, J., Bueno, L. Gastroenterology (1992) [Pubmed]
  17. Cholecystokinin induces cerebral vasodilatation via presynaptic CCK2 receptors: new implications for the pathophysiology of panic. Sánchez-Fernández, C., González, C., Mercer, L.D., Beart, P.M., Ruiz-Gayo, M., Fernández-Alfonso, M.S. J. Cereb. Blood Flow Metab. (2003) [Pubmed]
  18. Mutations within the cholecystokinin-B/gastrin receptor ligand 'pocket' interconvert the functions of nonpeptide agonists and antagonists. Bläker, M., Ren, Y., Gordon, M.C., Hsu, J.E., Beinborn, M., Kopin, A.S. Mol. Pharmacol. (1998) [Pubmed]
  19. Analysis of variation in L-365,260 competition curves in radioligand binding assays. Harper, E.A., Roberts, S.P., Shankley, N.P., Black, J.W. Br. J. Pharmacol. (1996) [Pubmed]
  20. L-365,260 inhibits in vitro acid secretion by interacting with a PKA pathway. Oiry, C., Pannequin, J., Cormier, A., Galleyrand, J.C., Martinez, J. Br. J. Pharmacol. (1999) [Pubmed]
  21. Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway. Crawley, J.N. J. Neurosci. (1992) [Pubmed]
  22. Novel gastrin receptors mediate mitogenic effects of gastrin and processing intermediates of gastrin on Swiss 3T3 fibroblasts. Absence of detectable cholecystokinin (CCK)-A and CCK-B receptors. Singh, P., Owlia, A., Espeijo, R., Dai, B. J. Biol. Chem. (1995) [Pubmed]
  23. Cholecystokinin type B receptor antagonist PD-136,450 is a partial secretory agonist in the stomach and a full agonist in the pancreas of the rat. Schmassmann, A., Garner, A., Flogerzi, B., Hasan, M.Y., Sanner, M., Varga, L., Halter, F. Gut (1994) [Pubmed]
  24. The gastrin-receptor antagonist L-365,260 inhibits stimulated acid secretion in humans. Murphy, M.G., Sytnik, B., Kovacs, T.O., Mertz, H., Ewanik, D., Shingo, S., Lin, J.H., Gertz, B.J., Walsh, J.H. Clin. Pharmacol. Ther. (1993) [Pubmed]
  25. Activation of amygdala cholecystokininB receptors potentiates the acoustic startle response in the rat. Frankland, P.W., Josselyn, S.A., Bradwejn, J., Vaccarino, F.J., Yeomans, J.S. J. Neurosci. (1997) [Pubmed]
  26. Binding sites and transduction process of the cholecystokininB receptor: involvement of highly conserved aromatic residues of the transmembrane domains evidenced by site-directed mutagenesis. Jagerschmidt, A., Guillaume, N., Roques, B.P., Noble, F. Mol. Pharmacol. (1998) [Pubmed]
  27. Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L-365,260. Bock, M.G., DiPardo, R.M., Evans, B.E., Rittle, K.E., Whitter, W.L., Veber, D.E., Anderson, P.S., Freidinger, R.M. J. Med. Chem. (1989) [Pubmed]
  28. Stimulation of mucus glycoprotein biosynthesis in rat gastric mucosa by gastrin. Ichikawa, T., Ishihara, K., Saigenji, K., Hotta, K. Biochem. Pharmacol. (1993) [Pubmed]
  29. Inhibition of the hypothalamic-pituitary-adrenal axis in food-deprived rats by a CCK-A receptor antagonist. Ruiz-Gayo, M., Garrido, M.M., Fuentes, J.A. Br. J. Pharmacol. (2000) [Pubmed]
  30. Evidence for an involvement of the brain cholecystokinin B receptor in anxiety. Singh, L., Lewis, A.S., Field, M.J., Hughes, J., Woodruff, G.N. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  31. Cholecystokinin type A and type B receptor antagonists produce opposing effects on cholecystokinin-stimulated beta-endorphin secretion from the rat pituitary. Millington, W.R., Mueller, G.P., Lavigne, G.J. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  32. Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production. Colucci, R., Blandizzi, C., Tanini, M., Vassalle, C., Breschi, M.C., Del Tacca, M. Br. J. Pharmacol. (2005) [Pubmed]
  33. A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260. Lotti, V.J., Chang, R.S. Eur. J. Pharmacol. (1989) [Pubmed]
  34. Effects of CCK antagonists on CCK-induced suppression of locomotor activity in mice. Hirosue, Y., Inui, A., Miura, M., Nakajima, M., Okita, M., Himori, N., Baba, S., Kasuga, M. Peptides (1992) [Pubmed]
  35. CCK-A and CCK-B receptors enhance olfactory recognition via distinct neuronal pathways. Lemaire, M., Barnéoud, P., Böhme, G.A., Piot, O., Haun, F., Roques, B.P., Blanchard, J.C. Learn. Mem. (1994) [Pubmed]
  36. Regulation of leptin distribution between plasma and cerebrospinal fluid by cholecystokinin receptors. Cano, V., Ezquerra, L., Ramos, M.P., Ruiz-Gayo, M. Br. J. Pharmacol. (2003) [Pubmed]
  37. Human pharmacokinetics and tolerability of L-365,260, a novel cholecystokinin-B antagonist. Grasing, K., Murphy, M.G., Lin, J., Swigar, M., Freedholm, D., Clarke, L., Zhang, J., Wolkowitz, O.M., Weingartner, H., Putnam, K., Seibold, J.R. Journal of clinical pharmacology. (1996) [Pubmed]
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