Disease relevance of U 50488

• Treatment of microglial cell cultures with U50,488 or U69,593 resulted in a dose-dependent inhibition of expression of the monocytotropic HIV-1 SF162 strain [1].
• Pretreatment with pertussis toxin (PTX) prevented the inhibition by U50,488 [2].
• The actions of the kappa 1 opioid agonist U-50,488 on presynaptic nerve terminals of the chick ciliary ganglion [3].
• Effects of pharmacological preconditioning with U50488H on calcium homeostasis in rat ventricular myocytes subjected to metabolic inhibition and anoxia [4].
• It is concluded that the kappa agonists PD117302 and U50488 produce a biphasic effect on 24 hr food intake, with an initial hyperphagia followed by a decrease in food intake [5].

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

• METHODS: Bremazocine, U69593, and U50488H were administered prior to amphetamine and cocaine, and locomotor activity was measured [16].
• In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity [17].
• The kappa-receptors coupled to G(i/o)proteins since pertussis toxin significantly reduced the U50488H actions on intracellular Ca(2+) and cAMP [18].
• In the present study, we examined the effects of the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) on HIV-1 expression in CD4+ lymphocytes, the main target cell of this virus [19].
• We used a vaccinia virus-based assay to measure the effects of U50,488 treatment of CD4(+) lymphocytes on HIV-1 IIIB Env glycoprotein-mediated fusogenic activity, based on the cytoplasmic activation of a reporter gene [20].

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].

References