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101.
M C Fournié-Zaluski E Lucas-Soroca J Devin B P Roques 《Journal of medicinal chemistry》1986,29(5):751-757
A stereospecific synthesis of thiorphan [N-[2(RS)-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] and retro-thiorphan [3-[[1(RS)-(mercaptomethyl)-2-phenylethyl]amino]-3-oxopropanoic acid], two highly potent inhibitors of enkephalinase, a neutral endopeptidase involved in enkephalin metabolism, is reported. Due to a rapid isomerization process, derivatives of retro-thiorphan, which contains a 2-substituted malonyl moiety, cannot be separated by classical methods. However, a separation of the diastereoisomeric mixtures of these retro-thiorphan derivatives was achieved by HPLC. The absolute configuration of each isomer was determined by using an NMR configurational correlation. The inhibitory potency of the various inhibitors indicates that, in the thiorphan series, the affinity for enkephalinase is independent of the stereochemistry of the 2-(mercaptomethyl)-1-oxo-3-phenylpropyl moiety. In contrast, in the retro-thiorphan series a 100-fold difference in the inhibitory activity of the two enantiomers is observed. This indicates that there are large differences in the conformational behavior of the two series of inhibitors at the active site of the enzyme. 相似文献
102.
Delta-opioid mediated inhibitions of acute and prolonged noxious-evoked responses in rat dorsal horn neurones.
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1. The effects of a selective delta-opioid agonist Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBULET) were examined on the C- and A beta-evoked responses of convergent dorsal horn neurones in the halothane anaesthetized, intact rat. 2. Intrathecal DSTBULET produced selective dose-dependent inhibitions of electrically-evoked C fibre responses of both superficial and deep neurones. A near-complete inhibition of 83 +/- 5% followed 100 micrograms of DSTBULET and the ED50 was 9 micrograms (13.5 nmol). Inhibitions were antagonised by intrathecal naloxone and ICI 174,864 but were not antagonised by pretreatment with intrathecal beta-funaltrexamine at a dose that blocked mu-opioid effects. By contrast, DSTBULET produced excitations of electrically-evoked responses of cells recorded in a zone intermediate between the superficial and deep neurones. 3. DSTBULET (50 micrograms) was also tested on the more prolonged noxious neuronal response produced by subcutaneous formalin (5%, 50 microliters) into the receptive field. DSTBULET profoundly inhibited the response to formalin. Pretreatment with ICI 174,864 before DSTBULET antagonised the effects of the delta-agonist on the formalin response. 4. The full peptidase inhibitor kelatorphan, known to protect endogenous enkephalins, was also tested on the formalin response. The intrathecal administration of 50 micrograms kelatorphan has previously been shown to inhibit electrically-evoked C fibre resonses of dorsal horn neurones and to be antagonised by ICI 174,864. The same dose of kelatorphan inhibited the formalin response in the present study. 5. From this study it appears that the delta-opioid agonist DSTBULET can produce profound inhibitions of the responses of convergent neurones to nociceptive afferent inputs. Furthermore, activation of delta-opioid receptors either by DSTBULET, or by protection of endogenous enkephalins with kelatorphan, can inhibit a more prolonged chemically-evoked nociceptive input onto these dorsal horn neurones. 相似文献
103.
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105.
Robertson RT; Gallardo KA; Claytor KJ; Ha DH; Ku KH; Yu BP; Lauterborn JC; Wiley RG; Yu J; Gall CM; Leslie FM 《Cerebral cortex (New York, N.Y. : 1991)》1998,8(2):142-155
The role of basal forebrain-derived cholinergic afferents in the
development of neocortex was studied in postnatal rats. Newborn rat pups
received intraventricular injections of 192 IgG-saporin. Following survival
periods ranging from 2 days to 6 months, the brains were processed to
document the cholinergic lesion and to examine morphological consequences.
Immunocytochemistry for choline acetyltransferase (ChAT) and in situ
hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the
cholinergic neurons in the medial septum and nucleus of the diagonal band
of Broca in the basal forebrain. In situ hybridization for glutamic acid
decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons.
Acetylcholinesterase histochemistry demonstrates a marked reduction of the
cholinergic axons in neocortex. Cholinergic axons are reduced throughout
the cortical layers; this reduction is more marked in medial than in
lateral cortical areas. The thickness of neocortex is reduced by
approximately 10%. Retrograde labeling of layer V cortico-collicular
pyramidal cells reveals a reduction in cell body size and also a reduction
in numbers of branches of apical dendrites. Spine densities on apical
dendrites are reduced by approximately 20-25% in 192 IgG- saporin-treated
cases; no change was detected in number of spines on basal dendrites. These
results indicate a developmental or maintenance role for cholinergic
afferents to cerebral cortical neurons.
相似文献
106.
107.
Trimetrexate (TMTX) is an anticancer drug with potential advantages over the more commonly used antifolate, methotrexate (MTX); however, its use has been limited by severe myelosuppression. Retroviral vectors containing mutant dihydrofolate reductase (DHFR) genes have been used to protect bone marrow cells from MTX, suggesting a similar approach could be used for TMTX. We first screened six variants of human DHFR to determine which allowed maximal TMTX resistance in fibroblasts. A variant enzyme containing a Leu-to-Tyr mutation in the 22nd codon (L22Y) was best, allowing a 100-fold increase in resistance over controls. Murine hematopoietic progenitor cells transduced with an L22Y- containing retroviral vector also showed high-level TMTX resistance in vitro. Mice reconstituted with L22Y-transduced bone marrow cells were challenged with a 5-day course of TMTX to determine whether hematopoiesis could be protected in vivo. Transfer of the L22Y vector resulted in consistent protection from TMTX-induced neutropenia and reticulocytopenia at levels that correlated with the proviral copy number in circulating leukocytes. We conclude that the L22Y vector is highly effective in protecting hematopoiesis from TMTX toxicity and may provide a means for increasing the therapeutic utility of TMTX in certain cancers. 相似文献
108.
Zusammenfassung Es wird über ein scapulo-peroneales Syndrom berichtet, dessen regellose, schubweise Entwicklung über Jahre von Schmerzen, distal betonten Paraesthesien sowie Hypaesthesien im Bereich der Hände und Unterschenkel begleitet wurde. Asymmetrische Paresen und Atrophien betreffen besonders den Schultergürtel sowie Fuß- und Zehenextensoren, wohingegen die Beuger verschont sind.Nach klinischem Befund, elektromyographischen und -neurographischen Untersuchungen sowie den Ergebnissen der Muskel- und Nervenbiopsie (N. suralis) wird das Syndrom in die Gruppe des Dawidenkowschen Typs der scapulo-peronealen Amyotrophie mit autosomal dominantem Erbgang eingeordnet.Auf differentialdiagnostische Fragen, die sich aus der Kombination des myopathischen Prozesses mit polyneuropathisch begrenzten Sensibilitätsstörungen und Reflexabschwächung ergeben, wird anhand ähnlicher Beobachtungen in der Literatur eingegangen.
The differential diagnosis of scapuloperoneal amyotrophy
Summary This report deals with a scapuloperoneal syndrome which developed simultanously with pain and distal paresthesias. In addition there was a slight sensory disturbance of glove and stocking type distribution. Motor conduction velocity was within normal limits and all distal latencies of response were normal; only the sensory conduction velocity of the left median nerve was found to be decreased (42.1 m/s). Electromyographic investigations revealed only signs of myopathy.Histological findings (m. deltoideus, m. tibialis anterior) favoured a primary myopathic process. Biopsy of the n. suralis revealed no certain pathological changes. The affection appears to have an autosomal dominant mode of inheritance.The sensory disturbance and decreased reflexes indicate an involvement of the nervous system, but the question of relationship to the scapuloperoneal muscular atrophy cannot yet be answered.相似文献
109.
C Deville X Roques G Fernandez N Laborde E Baudet F Fontan 《European journal of cardio-thoracic surgery》1988,2(3):185-191
Our experience (January 1982-May 1987) concerns 41 patients, operated upon for aortic dissection (30 patients) or aneurysm (11 patients) using circulatory arrest with deep hypothermia. There were 24 male and 17 female patients (mean age: 55 years 9 months, range 32-73 years). The mean circulatory arrest time in minutes was 41 +/- 3 (mean rectal temperature before circulatory arrest was 18.4 degrees C +/- 0.3 degrees C). Total (24 patients) or partial (16 patients) replacement of the aortic arch was performed. One patient with a sacciform aneurysm had the aortic wall defect closed. Hospital mortality was 22% +/- 7% (9 patients): 8 of 30 patients with aortic dissection (26.6%) and 1 of 11 patients with aortic aneurysm (9%). Neurological complications occurred in 3 patients. These data lead us to prefer circulatory arrest with deep hypothermia as the method of choice for aortic arch surgery. However, when a short circulatory arrest time (less than 30 min) for the repair is foreseeable, mild hypothermia (20 degrees C-24 degrees C) may be preferred. In patients who will not tolerate excessive cardiopulmonary bypass times, expected difficulties with the repair should suggest mild hypothermia and short circulatory arrest in easier cases or moderate hypothermia with brachiocephalic perfusion in the others. 相似文献
110.
Synthesis and biological activity of CCK26-33-related analogues modified in position 31 总被引:1,自引:0,他引:1
I Marseigne A Dor D Bégué M Reibaud J L Zundel J C Blanchard D Pélaprat B P Roques 《Journal of medicinal chemistry》1988,31(5):966-970
The role of the amino acid in position 31 of cholecystokinin CCK26-33 in the recognition of central and peripheral receptors was investigated by replacement of methionine-31 by amino acids with side chains of various chemical nature. Thus, phenylalanine, alanine, glutamic acid, and ornithine and its analogue with the epsilon-amino group protected by a benzyloxycarbonyl group were introduced as X residues in Boc(Nle28,X31)-CCK27-33 since the related analogue Boc(Nle28,Nle31)-CCK27-33 was shown to be equipotent to CCK26-33. The binding properties to both mouse brain membranes and guinea pig pancreatic acini and the peripheral activities (amylase secretion and contractile potency on guinea pig ileum) were determined. Whereas the introduction of phenylalanine, alanine, or ornithine residues in position 31 led to compounds that still displayed peripheral agonist properties, the presence of a negative charge in the side chain of the amino acid in position 31 prevented the binding of the peptide to both pancreatic and brain binding sites. Introduction of Phe31 and Ala31 residues increased the specificity of the peptides for the central receptors. Interestingly, when the amine function in the side chain of the ornithine-31 was protected by a benzyloxycarbonyl group, an unusual high affinity for pancreatic binding sites was observed and the related analogue proved to be a new peripheral CCK antagonist. 相似文献