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121.
P2Y受体(P2YRs)是一类由胞外核苷酸活化的G蛋白偶联受体(GPCRs),从属于嘌呤受体家族。P2Y受体的生理激动剂包括三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、三磷酸尿苷(UTP)、二磷酸尿苷(UDP),核苷酸糖和二核苷酸等。P2Y受体在机体组织内广泛表达,在免疫应答中发挥着重要作用。近年来随着研究深入,P2Y受体在炎症、癌症、心血管和神经退行性疾病中显示出作为药物靶标的巨大潜力,P2Y受体的研究对新药的进一步开发有着重要的意义。本文就P2Y受体的分类、结构,药理学特性及以P2Y受体为靶点的潜在药物等作一综述。 相似文献
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目的探讨不同保存液保存大鼠肝脏后离体再灌注时嘌呤核苷磷酸酶(PNP)活性和透明质酸吸收率的变化及意义。方法分别采用UW液、HTK液和Celsior液灌洗、冷保存Wistar大鼠肝脏16及24 h,然后用37℃的Kreb-Henseleit液在常温下连续灌注90 min,分别于灌注0、15、30、60和90 min时,从灌注液中取样,测定嘌呤核苷磷酸酶活性和外源性透明质酸吸收率的变化,据此评价肝窦内皮细胞的状况。结果经过16 h的低温保存,在再灌注60 min以前,HTK液组灌注液中PNP的含量明显高于UW液组和Celsior液组(P<0.01);再灌注60 min后,HTK液组和Celsior液组灌注液中PNP的含量明显高于UW液组(P<0.01)。经过24 h的低温保存,在再灌注15 min后,HTK液组灌注液中PNP含量明显高于Celsior液组(P<0.01),而Celsior液组又明显高于UW液组(P<0.01)。透明质酸的吸收率均为负值,说明内源性透明质酸的释放大于外源性透明质酸的吸收,且随着保存时间和再灌注时间的延长,这一趋势更加明显,其中HTK液组最明显,Celsior液组次之。结论随着低温保存和再灌注时间的延长,肝脏中PNP活性逐渐升高,外源性透明质酸的吸收率下降,二者可作为评价肝脏缺血-再灌注损伤的指标。 相似文献
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Extracellular recordings were made from the CA1 pyramidal cell layer of hippocampal slices in response to stimulation of Schaffer collateral fibres in stratum radiatum. Alphaxalone and 5α-pregnan-3α-ol-20-one potentiated the inhibitory effect of muscimol on the population spike size at low concentrations (0.5 and 1 μM) that had no significant effect on the spike size by themselves. This profile is in agreement with other reports which have described the effect of these neurosteroids as barbiturate-like. Alphaxalone and 5α-pregnan-3α-ol-20-one also at low concentrations potentiated the inhibitory effect of adenosine alone and in the presence of 1 mM barium which blocked adenosine activated potassium channels. Alphaxalone failed to potentiate the inhibitory effect of adenosine in the presence of 1 μM bicuculline. It is concluded that these neurosteroids enhanced the potentiative interaction between adenosine and muscimol in the presence of barium. The results indicate that adenosine's effects are normally enhanced by virtue of the potentiative interaction occurring with endogenous GABA. 相似文献
126.
H.Anne Simmonds Roland J. Levinsky David Perrett Dianne R. Webster 《Biochemical pharmacology》1982,31(6):947-951
A reciprocal relationship between erythrocyte ATP and deoxy-ATP levels has been noted in an immunodeficient child with adenosine deaminase (ADA) deficiency during therapy with red cell transfusions. The sum of red cell ATP plus deoxy-ATP equalled the normal complement of ATP prior to any form of therapy. dATP, dADP and dAMP levels were found in the same ratio (10:1:0.1) as the adenine nucleotides ATP, ADP and AMP. Red cell ATP levels were low, not high or normal as found by others in ADA deficiency, but no deoxyadenosine nucleotides could be found in peripheral blood mononuclear cells.Erythrocyte ATP depletion has recently been identified as a serious consequence of anti-leukaemic therapy with ADA inhibitors; it may thus be an important but hitherto unrecognised contributing factor in the clinical expression of inherited ADA deficiency. 相似文献
127.
John C. Wu 《Perspectives in Drug Discovery and Design》1994,2(1):185-204
Summary Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is investigated in clinical trials for the prevention of organ and tissue rejection in transplantation. Esterification of MPA to the prodrug MMF improves its bioavailability. MMF prolongs allograft survival and reverses ongoing rejection in animal studies, and has shown preliminary efficacy in human clinical trials in combination with established therapies for transplantation. The immunosuppressive activity of MPA results from the potent reversible inhibition of IMP dehydrogenase (IMPDH). Inhibition of IMPDH by MPA causes the depletion of intracellular GTP pools and inhibits proliferation of lymphocytes. IMPDH is the first enzyme in the committed pathway of de novo synthesis of guanine nucleotides. Two isoforms of human IMPDH are known. The type I enzyme is constitutively expressed, while the type II isozyme is induced in activated lymphocytes and other proliferating cells. MPA inhibits the type II enzyme with fivefold greater affinity than the type I enzyme (Ki=7 nM against type II IMPDH). Against the human enzymes, the kinetics of inhibition by MPA are uncompetitive with respect to both substrates IMP and NAD. Uncompetitive inhibition indicates that MPA preferentially binds to the enzyme after substrates, perhaps to an enzyme-IMP-NAD ternary complex or to an enzyme-XMP binary complex in the product side of the reaction. Uncompetitive inhibition by MPA cannot be overcome by increases in intracellular concentrations of the substrates. The immunosuppressive mechanisms of MPA are discussed in relation to lymphocyte proliferation, alterations of pools of other nucleotides coincident with GTP depletion, and inhibition of other GTP-dependent biochemical events. 相似文献
128.
The effects of chronic treatment of mice with clonazepam have been examined on the responses of neocortical slices to adenosine, 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA). Responses to these agonists were measured as changes in the depolarisation induced byN-methyl-d-aspartate (NMDA). Added to the superfusion medium diazepam blocked responses to adenosine but not 5-HT; this effect was not observed with 2-chloroadenosine or in the presence of 2-hydroxynitrobenzylthioguanosine. GABA was inactive in control slices but chronic treatment with clonazepam induced responses to GABA and enhanced responses to adenosine but not 5-HT. It is suggested that the induction of GABA responses may reflect the up-regulation of GABA receptors, but the increase of adenosine responses by clonazepam implies that there is no simple relationship between adenosine receptor binding and functional responses. 相似文献
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Pyrazolopyrimidine metabolism in the pathogenic trypanosomatidae 总被引:5,自引:0,他引:5
Pyrazolopyrimidines are purine analogues. These compounds are metabolized by the pathogenic hemoflagellates and other members of the family Trypanosomatidae as though they were purines. This metabolic sequence does not exist in man or other mammals. In the hemoflagellates, the pyrazolopyrimidine base, of which allopurinol is the paradigm, undergoes ribosylphosphorylation to the ribonucleotide. This ribonucleotide may remain as such or be aminated to the amino analogue and further converted to the aminopyrazolopyrimidine ribonucleoside triphosphate. The latter is incorporated into RNA. This metabolic sequence has been demonstrated in the genera Leishmania and Trypanosoma. 相似文献