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)

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

Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and mostnotablyin theacetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.
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PMID:Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide. 1193 42