Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone (N-CPM-MET-CAMO) were tested in opioid receptor binding assays and in the mouse tail-flick test in order to characterize the affinity, selectivity and antinociceptive properties of these two compounds. Incubating bovine striatal membranes with either MET-CAMO or N-CPM-MET-CAMO produced a wash-resistant, concentration- and time-dependent inhibition of the binding of the mu-selective ligand, [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin, but with no change in delta or kappa binding. Preincubating membranes with N-CPM-MET-CAMO decreased the maximum binding value for [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin binding without changing the Kd value. In the mouse tail-flick assay, MET-CAMO and N-CPM-MET-CAMO did not produce any antinociception up to a dose of 100 nmol after i.c.v. administration. However, pretreatment of mice with either compound produced a time- and dose-dependent antagonism of morphine-induced antinociception. Analgesia mediated by delta or kappa opioids was not altered by either MET-CAMO or N-CPM-MET-CAMO at a dose of up to 100 nmol. The mu antagonistic effect of 1 nmol of MET-CAMO and N-CPM-MET-CAMO appeared at 8 hr and lasted up to 72 hr, with a maximal effect at 16 to 24 hr after i.c.v. administration. Pretreatment of mice with 1 nmol of MET-CAMO or N-CPM-MET-CAMO, given by i.c.v. administration at -24 hr, produced a rightward and downward shift of dose-response line of i.c.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone: mu-selective irreversible opioid antagonists. 751 Nov 63

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) suppressed morphine-induced antinociception but had no effect on antinociception mediated by delta- or kappa-opioid receptors after a single i.c.v. 1-nmol injection from 8 to 72 h before testing. MET-CAMO had no agonist effects in the mouse tail-flick assay in doses up to 100 nmol. MET-CAMO is the first N-methylated morphine derivative which shows such long-lasting mu-selective opioid receptor antagonism with no agonistic properties.
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PMID:5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone: a long-lasting mu-opioid receptor antagonist devoid of agonist properties. 767 76

Neutral endopeptidase 24.11 (NEP; "enkephalinase") may inactivate a number of centrally active neuropeptides including the enkephalins and substance P. In most areas of the central nervous system, the cell types which express NEP activity are not known. The hypoglossal nucleus (N.XII) was selected as a model system to characterize the cytochemical localization of NEP. The effect of hypoglossal nerve axotomy upon the distribution of NEP activity in the hypoglossal nucleus was compared to the effect upon cholinergic markers, the mu opiate receptor, and the enkephalins. By use of a fluorescence histochemical method, NEP was localized at all levels of N.XII to the soma and proximal processes of the majority of the apparent motor neurons in the nucleus. Fluorescent double-labeling studies revealed the presence of numerous enkephalinergic varicosities which localized to the neuropil surrounding NEP-stained motor neurons. To determine whether NEP was synthesized by these motor neurons, 18 rats received a unilateral transection of the hypoglossal nerve. A pronounced decrease in NEP staining in N.XII was observed on the operated side as early as 3 days following axotomy. This decrease persisted at all levels of the nucleus for about 5 weeks. By 7 weeks, the staining between the control and operated sides was indistinguishable. By contrast, there was no apparent change in the density or distribution of enkephalin-immunoreactive varicosities in five animals examined 6 to 32 days following axotomy. Radioligand binding of [3H]DAMGO to the mu-opiate receptor in N.XII was studied in 20 animals by quantitative autoradiography at 2, 6, and 11 days after axotomy. No significant changes in the level of radioligand binding to the mu-receptor were detected in response to axotomy. In contrast to the opiate system, the cholinergic enzymes choline acetyltransferase, acetylcholinesterase, and pseudocholinesterase showed a coordinate decrease in motor neuron-associated staining on the operated side of N.XII at 3, 6, and 11 days following axotomy which paralleled the decrease in NEP staining. By contrast, the lysosomal enzyme marker, acid phosphatase, showed a pronounced increase in staining on the operated side. The results of this study are consistent with the synthesis of NEP by cholinergic N.XII motor neurons and indicates that the enkephalins and NEP in N.XII are closely associated, but derive from separate neuronal populations. The widespread overlap in the distribution of NEP-stained motor neurons and enkephalinergic varicosities in N.XII provides additional anatomical support for a potential role for NEP in the inactivation of centrally active enkephalins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential response of neutral endopeptidase 24.11 ("enkephalinase"), and cholinergic and opioidergic markers to hypoglossal axotomy. 820 Oct 16

The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.
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PMID:14 beta-Chlorocinnamoylamino derivatives of metopon: long-term mu-opioid receptor antagonists. 905 44

Morphine sulfate causes immunomodulatory and immunosuppressive effects in human. In this study, the signaling pathway involved in these morphine effects was studied. Addition of morphine sulfate to human CEMx174 lymphocytic cells resulted in increased expression of mitogen-activated protein kinase cascade proteins. Morphine enhanced the cellular levels of ERK1 (44 kDa), ERK2 (42 kDa), a 54-kDa ERK, MEK1 (45 kDa), and MEKK (78 kDa). A time-dependent increase in the activated (Thr and Tyr dually phosphorylated) state of ERK1 and ERK2 was also observed. Naloxone, a morphine antagonist, reversed the observed morphine effects, implicating a micro opioid receptor-mediated process. These findings suggest that mitogen-activated protein kinases are important intermediates in signal transduction pathways initiated by morphine receptors in immune cells.
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PMID:Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. 934 Nov 10

A new type of kappa-agonist, 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride (1, TRK-820), was discovered by a new working hypothesis. The "message-address concept" for opioid antagonists and the "accessory site" for general antagonists were applied to design TRK-820. A unique structural feature of TRK-820, which is different from other prototypical kappa-opioid receptor agonists, is the existence of the 4,5-epoxymorphinan structure with a tyrosine-glysine moiety for endogenous opioid peptides such as dynorphins. TRK-820 exhibited high potency and high kappa-selectivity in guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. In the mouse acetic-acid-induced writhing model and mouse tail flick model of antinociception, TRK-820 was 85-140 times more potent than morphine and 85-350 times more potent than U-50488H. This structurally novel kappa-agonist showed neither aversion nor preference in the Conditioned Place Preference test, in spite of the fact that prototypes of kappa-agonists (U-50488H derivatives) demonstrated aversion.
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PMID:Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan. 950 72

There is convincing evidence that genetic factors contribute to the predisposition to alcoholism. In this respect, alcohol-preferring (like C57BL/6 mice) and alcohol-avoiding lines (like DBA/2 mice) of animals served as models in the search for neurobiological substrates of excessive ethanol consumption. One of the systems that is thought to be associated with the incidence of alcoholism is the endogenous opioid system. In the first experiment, basal mRNA levels of mu- and delta-opioid receptors, and of opioid-degrading enzymes enkephalinase (neutral endopeptidase 24.11; NEP) and angiotensin-converting enzyme (ACE) in the brain regions of C57BL/6 and DBA/2 mice did not reveal genetically determined differences in these parameters between the two strains. Furthermore, in the brain regions studied, the corresponding enzyme activities of NEP and ACE did not differ significantly between the lines of mice, except for a higher NEP activity in the striatum and olfactory bulb of DBA/2 mice (p < 0.01). In the second experiment, C57BL/6 and DBA/2 mice were offered a free choice between water and 10% ethanol solution for 4 weeks and were killed thereafter; from another group, ethanol was removed for 3 days and from a third group ethanol was removed for 3 weeks before killing. In the striatum, a highly significant increase in the ACE mRNA amount was detected after 3 weeks of removal of ethanol in C57BL/6 mice, whereas in DBA/2 mice the delta-opioid receptor mRNA level was increased at this time when compared with the corresponding ethanol treatment group. The most striking changes were seen in the hypothalamus, where mu-opioid receptor, ACE, and NEP mRNA amounts markedly decreased after ethanol treatment in both strains. Thus, chronic ethanol intake caused significant changes in the gene expression of distinct components of the endogenous opioid system. These findings further underline an involvement of the opioid system in the effects of ethanol.
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PMID:Effect of ethanol drinking on the gene expression of opioid receptors, enkephalinase, and angiotensin-converting enzyme in two inbred mice strains. 975 41

Receptors coupled to pertussis toxin (PTX)-sensitive Gi proteins regulate T lymphocyte cytokine secretion, proliferation, and chemotaxis, yet little is known about the molecular mechanisms of Gi protein signaling in mammalian lymphocytes. Using the Jurkat T lymphocyte cell line, we found that a stably expressed Gi protein-coupled receptor (the delta-opioid receptor (DOR1)) stimulates MEK-1 and extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and transcriptional activity by an ERK target, Elk-1, via a mechanism requiring a PTX-sensitive Gi protein. Levels of beta-adrenergic receptor kinase-1 C-terminal fragment that inhibited signaling by Gi protein beta gamma subunits in these cells had no effect on DOR1 stimulation of either MEK-1- or Elk-1-dependent transcription, indicating that this pathway is independent of beta gamma. Analysis of this betagamma-independent pathway indicates a role for a herbimycin A-sensitive tyrosine kinase. Unlike beta gamma-mediated pathways, the beta gamma-independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The beta gamma-independent pathway regulates downstream events, since blocking it abrogated both Elk-1-dependent transcription and mobilization of the mitogenic transcription factor, AP-1, in response to DOR1 signaling. These results characterize a novel, Ras- and PI 3kinase-independent pathway for ERK activation by Gi protein signaling that is distinct from ERK activation by beta gamma and may therefore be mediated by the alphai subunit.
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PMID:Gi proteins use a novel beta gamma- and Ras-independent pathway to activate extracellular signal-regulated kinase and mobilize AP-1 transcription factors in Jurkat T lymphocytes. 1039 49

We analyzed the pharmacological properties of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6b eta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors and human nociceptin receptor. TRK-820 showed high affinity for the kappa-opioid receptor, with a Ki value of 3.5 +/- 0.9 nM. In CHO cells expressing kappa-opioid receptors, TRK-820 inhibited forskolin-stimulated cAMP accumulation, and the maximal inhibitory effect was equivalent to that of (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), a full agonist of kappa-opioid receptor. In CHO cells expressing mu-opioid receptors, TRK-820 inhibited cAMP accumulation, but the maximal inhibitory effect was significantly smaller than that of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), a full agonist of mu-opioid receptor. In CHO cells expressing delta-opioid receptor, the inhibitory effect of TRK-820 on cAMP accumulation was very weak. Using site-directed mutagenesis, the high affinity of TRK-820 for the kappa-opioid receptor was revealed to require Glu297. TRK-820 bound to the nociceptin receptor with a Ki value of 380 +/- 50 nM. TRK-820 by itself had no effect on cAMP accumulation in CHO cells expressing nociceptin receptors, but significantly antagonized the nociceptin (10 nM)-mediated inhibition of cAMP accumulation at high concentrations. These results indicate that TRK-820 acts as a full agonist for the kappa-opioid receptor, a partial agonist for the mu-opioid receptor and a low-affinity antagonist for the nociceptin receptor.
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PMID:Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor. 1044 Jan 1

TRK-820, a new type of 4,5-epoxymorphinan derivative, was investigated in vivo for antinociceptive activities and its selectivity on various opioid receptors in mice. TRK-820 given s.c. or p.o. was found to be 351- and 796-fold more potent than U50,488H with acetic acid-induced abdominal constriction test. The duration of the antinociceptive effect produced by TRK-820 was longer than that produced by mu-opioid receptor agonist morphine or other kappa-opioid receptor agonists. In addition, with four other antinociceptive assays, low temperature hot plate (51 degrees C), thermal tail flick, mechanical tail pressure and tail pinch tests, TRK-820 was also found to be 68- to 328-fold more potent than U-50488H, and 41- to 349-fold more potent than morphine in producing antinociception, as comparing the weight of the different compound. However, TRK-820 was less active in inhibiting the high temperature (55 degrees C) hot plate response. The antinociceptive effects produced by TRK-820 were inhibited by nor-BNI, but not by naloxone or naltrindole (NTI) with the abdominal constriction test, indicating that the antinociception is selectively mediated by the stimulation of kappa-, but not mu- or delta-opioid receptors. Co-administration of TRK-820 with morphine slightly enhanced the antinociception induced by morphine in the mouse hot plate test. On the other hand, pentazocine significantly reduced the morphine-induced antinociception. TRK-820 produced sedation at doses, which are much higher than the doses for producing antinociception. These results indicate that the potent antinociception induced by TRK-820 is mediated via the stimulation of kappa-, but not mu- or delta-opiod receptors.
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PMID:Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist. 1057 86


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