可溶性鸟苷酸环化酶刺激剂的设计、合成与生物活性评价

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1、万方数据广西医科大学硕士毕业论文DESIGN，SYNTHESISANDBIOLOGICALE、，rAI，UATl0NOFSOLUBLE(孔】．ANrYl，ATECYCLASESTIⅣⅡⅡ．ATORSABSTRACTSolubleguanylatecyclase(sGC)isakeyenzymeofNO--sGC--cGMPsignalpathway,anditistheonlyknownreceptorofNOuptodate．Onceactivated，sGCCancatalytizetheconversionofGTPtocGMP,whichwasusedas

2、thesecondmessengertotransmitsignalstothedownstreameffectorsincluding：ion-gatedchannels，proteinkinaSe，phosphodiesterase，andSOon，sothencauseaseriesofphysiologicalresponsessuchasintestinalperistalsis，vascularsmoothmusclerelaxation，decreasesinbloodpressure，braindevelopment,plateletaggrega

3、tionandcellproliferationandapoptosis【l】．Underphysiologicalconditions，NOissynthesizedbyendothelialnitricoxidesynthase(eNOS)，neuronalnitricoxidesynthase(nSOS)andinduciblenitricoxidesynthase(iNOS)catalyzingthedecompositionofL-arginineinceils．Inthearterialliningcells，NOwasmainlysynthesize

4、dbythecatalysisofeNOS，andquicklyspreadtothedeepvascularsmoothmuscletostimulateandactivatesGC．TheblockageofNO．·sGC—·eGMPsignalingpathwayisassociatedwiththepathophysiologyofmanydiseases，suchas：cardiovasculardisease，kidneydisease，lungdiseaseand气万方数据广西医科大学硕士毕业论文erectiledysfunction．Amongth

5、em，pulmonaryarterialhypertension(PAH)ismoreserious，andCanleadtoheartfailureandevendeathultimately．Currently,themajordrugsusedtotreatPAHpatientsinclinicalaredividedintothreecategories：endothelialreceptorantagonists，phosphodiesterase一5inhibitorsandprostacyclinanalogues．Theyaretorelievet

6、heprogressofthediseasebyrelaxingbloodvessels．However'theeffectofthetreatmentremainunsatisfactory、析Ⅱlpersistenthighmortality,insufficientclinicalimprovementandnoneconvincingreportofanyreversalofthediseaseprocess．VascularremodelingisconsideredtobethemaincauseofPAH．Thus，anti-vascularremo

7、delingisconsideredtoberelativelypromisingtreatment．Thismethodcouldreversetheprogressofthedisease，SOthenachievethepurposeofcuringPAH．Basedonthismethod，avarietyofdrugshavebeendeveloped，andthesedrugsmainlyexerttheirtherapeuticeffectsbythreeapproachs：vasodilation，anti-remodelingandanti-in

8、flamm