Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutral endopeptidase (EC 3.4.24.11) is an integral membrane protein found at the plasma membrane of many cell types and is especially abundant at the apical "brush border" membrane of the kidney proximal tubules. The enzyme consists of a short amino-terminal cytosolic domain of 27 amino acids, a single hydrophobic sequence which is believed to be responsible for anchoring the enzyme in the plasma membrane, and a large extracellular domain containing the active site. This model is consistent with the proposed function of neutral endopeptidase, which is believed to play an important role in the inactivation of small regulatory peptides at the cell surface. Site-directed mutagenesis has allowed the identification of 1 glutamic acid and 2 histidine residues essential for catalysis. All are located near the COOH terminus of the protein. We do not know, however, whether other segments of the protein are involved in the structure of the active site. The exact role of the cytosolic and transmembrane domains is also unknown. In this report, we have induced the secretion of a soluble form of recombinant neutral endopeptidase in COS-1 cells by fusing in-frame, the cDNA encoding the signal peptide of a secreted protein (pro-opiomelanocortin) to the cDNA sequences of the complete ectodomain of neutral endopeptidase. Characterization of the secreted recombinant protein indicated that it has the same catalytic properties as the membrane-bound recombinant enzyme or as the enzyme extracted from kidney brush border membranes. Thus the extracellular domain alone is sufficient for conferring full catalytic activity to neutral endopeptidase.
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PMID:Fusion of a cleavable signal peptide to the ectodomain of neutral endopeptidase (EC 3.4.24.11) results in the secretion of an active enzyme in COS-1 cells. 267 Sep 43

We have shown that a number of compounds which inhibit the degradation of met-enkephalin can produce naloxone-reversible analgesia in mice. These compounds also potentiate the analgesia produced by acupuncture, foot shock, and transcutaneous nerve stimulation in animals and humans. The potency of their effectiveness as analgesics or potentiators parallels their potency as inhibitors of mouse brain enkephalinase. D-Phenylalanine (DPA), one of these enkephalinase inhibitors, has been used successfully for the management of chronic intractable pain in humans and to potentiate the treatment of many painful conditions by acupuncture. Other aspects of pharmacology of DPA will be discussed, including its effects on the cardio-vascular system, behavior, and lack of development of tolerance and dependence when used chronically in animals and humans.
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PMID:Pharmacology of enkephalinase inhibitors: animal and human studies. 286 74

Endogenous opioid peptides, by modulating the release of sympathetic transmitters, may play a role in the pathogenesis of migraine and related headaches which are considered hypernociceptive syndromes. Hypoendorphinaemia has been demonstrated in migraine attack. Captopril, a drug able to potentiate morphine analgesia in rats and inhibit enkephalinase in animals and in man, improves the clinical course of migraine. In the present research the cerebrospinal fluid and plasma beta-endorphin (beta-EP) levels have been evaluated following a single oral dose of captopril. The drug increased plasma beta-EP levels in migraine sufferers, and these data may be relevant in the mechanism of action of this drug in migraine and related headaches.
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PMID:Hypernociceptive syndromes and pharmacological inhibition of endogenous opioid degradation. 294 84

Actinonin, previously isolated as an antibiotic and shown to be an inhibitor of aminopeptidase M (EC 3.4.11.2), has now been shown to inhibit three enkephalin-degrading enzymes from guinea-pig striatum. The values of IC50 were 0.39 microM for striatal membrane aminopeptidase ("enkephalin-aminopeptidase") and 5.6 microM striatal membrane neutral endopeptidase ("enkephalinase A"). Furthermore, soluble dipeptidylaminopeptidase in a rat whole brain homogenate was also inhibited by actinonin with the IC50 value of 1.1 microM. Actinonin administered intracisternally (i.cist., 50 micrograms) or intraperitoneally (i.p., 100 mg/kg), potentiated the analgesic action of met-enkephalin (50 micrograms i.cist.). analgesia by a tail-flick test. The potentiating activity of actinonin i.p. to met-enkephalin analgesia was almost the same potency as that of thiorphan, whereas the inhibitory activity of actinonin against enkephalinase A was 1/1000 that of thiorphan. Actinonin alone, administered either i.cist. or i.p., showed an analgesic action as estimated by the tail-flick test.
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PMID:Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes. 329 9

Recently, the presence and the concomitant release with catecholamines of metenkephalin and other pro-enkephalin A deriving peptides have been demonstrated in the adrenal medulla of various mammals and man. As high amounts of catecholamines are released in the newborn at delivery, probably following the stress of parturition, a similar release of met-enkephalin and other pro-enkephalin A deriving peptides from the newborn chromaffin tissue may be hypothesized. In the present study we investigate the occurrence of met-enkephalin-like immunoreactivity and enkephalinase (quite a specific enkephalin degrading enzyme) in cord and newborn plasma at different hours after birth. Our results show the presence of high met-enkephalin-like immunoreactivity levels in cord and newborn plasma with respect to normal adult values. On the contrary, cord blood enkephalinase activity was lower than in adult subjects and further decreased during the first hours of life. A positive correlation was found between the two parameters. These data seem to indicate a release of met-enkephalin-like peptides from the newborns' sympathoadrenal tissue following the stress of delivery and in the first hours of life.
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PMID:Met-enkephalin-like immunoreactivity (MELI) and enkephalinase activity (EKA) in cord blood and newborns in the first hours of life. 352 98

The present experiments show the presence of both metenkephalin-like and met-enkephalin-Arg6-Phe7-like immunoreactivity in the superior cervical ganglion of the cat; this was determined by radioimmunoassay after high-pressure liquid chromatography separation of tissue extracts. There was measurable efflux of both peptides, as determined by radioimmunoassay of ganglionic perfusates; this measure was increased by thiorphan, an enkephalinase inhibitor. The effect of the 2 peptides on ACh release was determined: The stable analog of methionine-enkephalin, D-Ala2-methionine-enkephalinamide, did not affect ACh release from the ganglion; in contrast, methionine-enkephalin-Arg6-Phe7 significantly depressed evoked ACh release. The effect of met-enkephalin-Arg6-Phe7 to decrease ACh release was antagonized, although only partially, by the opioid antagonist naloxone. Thus, it appears that methionine-enkephalin-Arg6-Phe7 alters ACh release from the superior cervical ganglion by acting, at least in part, on a presynaptic opioid receptor. The results suggest that in the cat superior cervical ganglion, the heptapeptide enkephalin might have a significant role in the regulation of synaptic transmission, which is unrelated to its potential function as a precursor for methionine-enkephalin.
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PMID:Effect of endogenous opioid peptides on acetylcholine release from the cat superior cervical ganglion: selective effect of a heptapeptide. 359 43

The effects of nineteen AHPA* derivatives were examined on morphine analgesia by tail-flick test in rats and on enkephalinase inhibition which was based on the formation of tyrosyl-glycyl-glycine from met-enkephalin. The correlation between the enhancement of morphine analgesia in vivo and enkephalinase inhibition in vitro was analyzed. The different analogs varied considerably in the degree of enhancement of morphine analgesia and inhibition of enkephalinase. A close relationship between enkephalinase inhibition expressed by IC50 in vitro and enhancement of morphine analgesia in vivo was observed in thirteen out of nineteen AHPA derivatives examined. One of other six AHPA derivatives which showed weak effectiveness in potentiating on morphine analgesia but was highly potent as an enkephalinase inhibitor, caused potent analgesic action when it was applied intracisternally indicating poor penetration of the blood brain barrier. The possibility was discussed that some of other compounds excluded from the linear relationship might act on other enkephalin degrading enzymes such as aminopeptidase.
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PMID:Relationship between enhancement of morphine analgesia and inhibition of enkephalinase by 2S, 3R 3-amino-2-hydroxy-4-phenylbutanoic acid derivatives. 612 60

In order to study the pharmacodynamic basis of therapeutic uses of placental extracts researches was carried out on Sephadex G25 factors of autolytic extract of human placenta. Four of these fractions showed immunoreactivity for both beta-endorphin and ACTH, and were able to stimulate lipolysis in rabbit adipose tissue. An inhibition of the enkephalinase activity of rat brain homogenates was displayed by placental fractions of low molecular weight. These results suggest that beta-endorphin and ACTH play a roles in the pharmacological activity of placental extracts.
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PMID:Lipolytic and enkephalinase inhibitory activities of polypeptides from placental autolysate prepared for therapeutic purposes. 627 79

The kinetics of the reactions of nine opioid peptides with the neutral endopeptidase ("enkephalinase") activities of human kidney, rat kidney, and rat brain have been determined. These opioid peptides can be divided into two classes, those that are good inhibitors of Leu5-enkephalin hydrolysis (Ki less than 75 microM) and good substrates for the enzyme, and those that are poor inhibitors (Ki greater than 500 microM) and are not substrates for the enzyme. The former group includes Leu5-enkephalin, Met5-enkephalin, Met5-enkephalin-Arg6-Phe7, beta-lipotropin, and gamma-endorphin, while the nonreactive opioid peptides include alpha-neo-endorphin, beta-neo-endorphin, dynorphin, and beta-endorphin. These results suggest that those peptides containing the Met5-enkephalin sequence are more reactive than those containing the Leu5-enkephalin sequence. The lack of specificity of this neutral endopeptidase indicates that it may function in the degradation of a variety of biologically active peptides.
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PMID:Reaction of opioid peptides with neutral endopeptidase ("enkephalinase"). 637 10

Opiates are known to be reinforcing when injected into the ventral tegmental area (VTA). The present study produced conditioned reinforcement with local injections of exogenous d-ala2-met5-enkephalinamide (DALA), a potent analogue of met-enkephalin, and with thiorphan , an enkephalinase inhibitor which protects endogenous opiates from enzymic degradation. In a conditioned place preference paradigm, rats received injections of DALA (1.0, 3.0, or 8.0 micrograms), thiorphan (60 micrograms), and/or naloxone (10 micrograms), or saline vehicle. Conditioned reinforcement was obtained with 8.0 micrograms of DALA and also with thiorphan but not with thiorphan plus naloxone. This suggests that reward can be generated by endogenous opiates in the VTA. Tests during the light phase and dark phase suggested that diurnal periodicity may play a role in opiate reward. It is concluded that the VTA can generate conditioned reward through transmitter-receptor interaction involving an endogenous opiate substrate which is probably enkephalinergic.
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PMID:Endogenous opiate reward induced by an enkephalinase inhibitor, thiorphan, injected into the ventral midbrain. 658 95


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