Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Azidothiorphan and its [14C]-labeled analogue have been developed as photoaffinity ligands for the active site of the neutral endopeptidase 24.11. In in vitro assays azidothiorphan inhibits the endopeptidase activity with a Ki of 0.75 nM. After ultraviolet irradiation the inhibitor binds irreversibly to the enzyme, and many factors suggest that the photolabeling occurs at the active site. The binding is accompanied by a loss of enzymatic activity, and the inclusion of the competitive inhibitor thiorphan protects the endopeptidase from this inactivation. In addition the binding of another competitive inhibitor [3H]N-[(R,S)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]-glycine to the active site of endopeptidase-24.11 is inhibited after irradiation with azidothiorphan. Experiments with [14C]-azidothiorphan have shown that very little nonspecific binding of inhibitor to enzyme occurs and the the labeled probe remains bound under denaturing conditions. Azidothiorphan has also been found to produce a long-lasting naloxone-reversible analgesia after intracerebroventricular administration. The results show that azidothiorphan should prove useful both for structural studies and for investigations on the synthesis and turnover of the neutral endopeptidase-24.11.
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PMID:Irreversible photolabeling of active site of neutral endopeptidase-24.11 "enkephalinase" by azidothiorphan and [14C]-azidothiorphan. 347 79

The endogenous opioid peptide enkephalin (EK) is known to be degraded mainly by two enzymes, the dipeptidyl carboxypeptidase 'enkephalinase' and aminopeptidase. Microinjection of the enkephalinase inhibitor thiorphan or the aminopeptidase inhibitor bestatin into the nucleus accumbens of the rabbit produced a dose-dependent analgesic effect. This analgesic effect was totally reversed by the narcotic antagonist naloxone or by antibodies against [Met5]enkephalin (MEK) administered to the same site. Antibodies against [Leu5]enkephalin were not effective. Moreover, microinjection of thiorphan or bestatin into the nucleus accumbens resulted in a marked potentiation of the aftereffect of electroacupuncture (EA) produced analgesia, as well as the analgesia induced by a small dose of morphine. It is concluded that the analgesic effect elicited by EA and morphine is mediated, at least in part, by MEK-like immunoreactive substance(s) in the nucleus accumbens.
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PMID:Electroacupuncture and morphine analgesia potentiated by bestatin and thiorphan administered to the nucleus accumbens of the rabbit. 348 2

Acetorphan, i.e. N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]-glycine, benzyl ester, is a lipophilic derivative of Thiorphan, a potent inhibitor of "enkephalinase" (EC 3.4.24.11). On purified enkephalinase its inhibitory potency was approximately 1000 fold less than that of Thiorphan but became close to the latter (nanomolar) when it was incubated previously with cerebral membranes. After parenteral administration to mice and rats (1-10 mg/kg) extensive inhibition of cerebral enkephalinase was shown by the depressed enzyme activity in brain membranes from treated animals and the long-lasting potentiation of analgesia elicited by (D-Ala2,Met5)enkephalin (i.c.v.). This suggests that acetorphan easily enters the brain where the active Thiorphan is released. Parenteral acetorphan elicited a series of naloxone-reversible, opioid-like effects, most of which were described previously with intracerebral Thiorphan or other enkephalinase inhibitors. Antinociceptive effects were found in some tests (hot plate jump and phenylbenzoquinone-induced writhing) but not in others (hot plate licking and tail withdrawal). "Antidepressant" effect was found in the "mouse despair" test and antidiarrhoeal effect in the rat castor oil test. Acetorphan also elicited significant increases and decreases in turnover indexes of serotonin and noradrenaline, respectively, in mouse cerebral cortex. In mice chronically treated with acetorphan, the antinociceptive activity of the compound was not modified markedly and no overt withdrawal symptom could be observed after either treatment interruption or administration of naloxone.
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PMID:Pharmacological properties of acetorphan, a parenterally active "enkephalinase" inhibitor. 351 39

The potencies of the R and S isomers of thiorphan and rigid analogs of thiorphan to produce analgesia in a mouse hot-plate assay have been compared with their potencies to inhibit enkephalin degradation by rat brain "enkephalinase A." The R and S isomers of thiorphan were equipotent as enzyme inhibitors (IC50 approximately 10(-9) M) but had significantly different analgesic profiles when injected i.c.v. Rigid analogs of thiorphan were less potent enzyme inhibitors (IC50 values of 10(-7) - 10(-4) M) but produced analgesia and potentiated Tyr-D-Ala-Gly-Phe-Met-NH2 induced analgesia at doses (i.c.v.) comparable to thiorphan. These observations suggest that inhibitors of enkephalinase A produce analgesia through a pharmacological mechanism which is not directly related to inhibition of enkephalin degradation.
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PMID:Thiorphan and analogs: lack of correlation between potency to inhibit "enkephalinase A" in vitro and analgesic potency in vivo. 389 20

New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to the general formula HC(O)N(OH)CH2CH(CH2Ph)CONHCH2COOH (compound 7) and HN(OH)C(O)CH2CH(CH2Ph)CONHCH(R)COOH (compound 11, R = H; compound 13, R = CH3) behave as full inhibitors of the three enzymes, with IC50's in the nanomolar range for enkephalinase, from 0.3 microM to 1 nM for dipeptidylaminopeptidase, and in the micromolar range for a biologically relevant aminopeptidase. Two diastereoisomers of the most active inhibitor 13 were separated by HPLC and their stereochemistry was assigned by 1H NMR spectroscopy. Both isomers were efficient as enkephalinase blockers, but only the RS isomer, designated kelatorphan, was able to strongly inhibit aminopeptidase and dipeptidylaminopeptidase. Intracerebroventricular injection in mice of these mixed inhibitors, especially kelatorphan, led to naloxone reversible analgesic responses (hot-plate test) that were slightly better than those produced by a mixture of thiorphan and bestatin, two potent inhibitors of enkephalinase and aminopeptidase, respectively. Kelatorphan was also more efficient in potentiating the analgesia induced by a subanalgesic dose of Met-enkephalin. All these results support a physiological role in pain transmission for enkephalinase and a probably synaptic aminopeptidase M.
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PMID:New bidentates as full inhibitors of enkephalin-degrading enzymes: synthesis and analgesic properties. 389 41

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

A number of compounds have been shown to inhibit the degradation of enkephalins. As expected, these compounds produce naloxone reversible analgesia and potentiate the analgesia produced by enkephalins and by acupuncture. One of these, D-phenylalanine, is also anti-inflammatory. D-phenylalanine has proven to be beneficial in many human patients with chronic, intractable pain. It is proposed the enkephalinase inhibitors may be effective in a number of human "endorphin deficiency diseases" such as depression, schizophrenia, convulsive disorders and arthritis. Such compounds may alleviate other conditions associated with decreased endorphin levels such as opiate withdrawal symptoms.
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PMID:D-phenylalanine and other enkephalinase inhibitors as pharmacological agents: implications for some important therapeutic application. 612 72

New carboxyalkyl compounds derived from Phe-Leu and Phe-Ala were synthesized and checked as inhibitors of "enkephalinase", a metalloendopeptidase cleaving the Gly3-Phe4 bond of enkephalins from mouse striatal membranes. Differential recognition of both brain enkephalinase and angiotensin-converting enzyme (ACE) catalytic sites by these carboxylalkyl compounds lead to potent (KI approximately 0.5 microM), competitive and selective inhibitors of the enkephalin-degrading enzyme. The most interesting compound, N-[(RS)-2-carboxy-3-phenylpropanoyl]-L-leucine (3, KI = 0.34 microM), is 10000 times more potent on enkephalinase than on ACE activities. Intracerebroventricular (icv) injection of 3 in mice leads to a high potentiation of the analgesic effect of the exogenously administered D-Ala2-Met-enkephalin, evidencing the in vivo inhibition of enkephalinase. Moreover, icv administration of 3 alone induces a dose-dependent analgesia in mice measured on both hot-plate and writhing tests. In the former assay, the ED50 was approximately 10 micrograms per animal, slightly higher than that of thiorphan. All the antinociceptive effects were antagonized by naloxone, demonstrating the involvement of enkephalins in analgesia and their in vivo protection from enkephalinase by 3. The described compounds can be considered as first examples of a new series of analgesics and potentially psychoactive agents.
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PMID:New carboxyalkyl inhibitors of brain enkephalinase: synthesis, biological activity, and analgesic properties. 629 20

The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.
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PMID:Effect of inhibition of neuropeptidases on the pain threshold of mice and rats. 636 60


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