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

• The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder [6].
• Devazepide in high doses (0.1-1 mg/kg IP) reduced spontaneous motor activity, whereas L-365,260 at a high dose (1 mg/kg IP) increased the activity of mice [7].
• We investigated, by c-Fos immunohistochemistry, the effect of CCK1 and CCK2 receptor antagonists (SR-27,897 and L-365,260, respectively) on c-Fos levels expression induced by food deprivation [8].
• Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model [9].
• In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal [9].

High impact information on L-365260

• The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed [10].
• The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety [10].
• Microinjection of the cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance [11].
• L-365,260, a CCK receptor B antagonist used at 0.01 microM, increased cellular proliferation in seven cell lines (A172, H4, Hs683, SW1783, T98G, U118, and U138), decreased it in one (U87), and had no effect in the remaining two [12].
• The effects of added gastrin (at 0.01, 0.1, and microM) and the gastrin/CCK antagonists L-365,260, CI-988, L-364,718, and JMV 234 (each at 0.01, 0.1, and 1 microM) on the cellular proliferation rates of the 10 cell lines were indirectly measured by use of the colorimetric tetrazolium assay [12].

Chemical compound and disease context of L-365260

• Following 10 days withdrawal, rats were injected with devazepide (0, 0.0001, 0.001, 0.01, 0.1, or 1.0 mg/kg) or L-365,260 (0, 0.001, 0.01, or 0.1 mg/kg) followed 30 min later by AMPH (0.75 mg/kg) and their locomotor activity recorded [13].
• RESULTS: L-365,260 levels were comparable to levels in earlier studies demonstrating inhibition of pentagastrin-stimulated acid secretion in normal subjects and blockade of anxiogenic effects of cholecystokinin injections in patients with panic disorder [14].
• L-740,093, L-365,260, LY-288513 and CI-988 administered alone did not alter spontaneous locomotor activity (motility) as compared to vehicle/saline controls [15].
• L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg) [9].

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

• Fourth, pretreatment with the CCKB receptor antagonist L-365,260 (0.1 mg/kg, i.p.) attenuated the potentiation of startle produced by intra-amygdala infusions of pentagastrin [25].
• Substitution of Phe347 in TM-VI with alanine produced a mutant receptor that displays the same affinity and selectivity as the wild-type receptor for agonists, but a slightly increased affinity for the selective CCKB antagonist L-365,260 [26].
• Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L-365,260 [27].
• Ranitidine, diphenhydramine and omeprazole at 10(-5) M did not suppress the tetragastrin-induced increase in [3H]GlcN incorporation into mucin, but L-365,260 at a concentration of 10(-6) M completely blocked this effect [28].
• Under these conditions we observed that the CCK-A receptor antagonist, SR-27897 (0.3 mg kg(-1)), but not the CCK-B receptor antagonist, L-365260 (1 mg kg(-1)), increases food-intake [29].

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

• Plasma levels of L-365,260 were determined by high pressure liquid chromatography [14].
• In contrast, the effect of caerulein, but not that of L-365,260, was abolished following a bilateral subdiaphragmatic vagotomy [35].
• Therefore, we administered SR-27897, a selective CCK1 receptor antagonist, and L-365260, a selective CCK2 receptor antagonist, to fed and food-deprived rats and determined plasma leptin concentration by enzyme immunoassay [36].
• Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia [9].
• L-365,260 had an acceptable tolerability profile after oral administration [37].

References