gabab受体变构调节剂cgp7930构效关系的分析-analysis of the structure-activity relationship of gabab receptor allosteric modulator cgp 7930.docx

检测的结果，分别总结出了R1-R5 不同基团位置的作用，并成功构建出了CGP7930构效关系图谱。并推测R1基团位置的羟基和R2基团位置的两个叔丁基支链是CGP7930识别GB2亚基位点所必需的；在CGP7930三维结构中，R5基团位置碳原子所连接的基团对CGP7930 的变构调节活性有关键的影响，改变该位置结构可能会使CGP7930 的特性发生改变，从而筛选获得更加高效和不同特性的药物。总之，我们对GABAB受体变构调节剂CGP7930构效关系图谱的建立，对我们下一步的改造优化提供了依据，同时对GABAB受体新药研发奠定了基础。关键词：GABAB受体；CGP7930；构效关系；药物筛选；变构调节剂AbstractGamma-aminobutyricacid(GABA)isthemajorinhibitoryneurotransmitterinthevertebrateCNS(centralnervoussystem),involvingmanyrelatedphysiologicalprocedures.ThemetabotropicGABAreceptortypeB(GABABR),whichbelongstothe G-proteincoupledreceptors(GPCR)mediatingslowlong-termdepressionisgenerallyconsideredtobeexcellentdrugtargets,withacomplexandrefinedmechanismofactivation.TraditionaldrugdevelopmenttargetedatGABABreceptorsisfocusedonagonists andantagonists,theuseofwhichislimitedbyitssideeffects,poorpharmacokinetics,andthedevelopmentoftolerance.Allostericmodulators,whichinteractwith binding sites topologically distinctfromtheorthostericligandbindingsites,canmodulatetheinteractionbetweensubunitsordomainsintheGABABheterodimer.PositiveandnegativeallostericmodulatorscanpotentiateordecreasetheactivityofGABABreceptorsrespectively,withimprovedselectivityandsafety,alongwithmaintenanceofspatialandtemporalaspectsofGABABreceptorssignaling.AllostericmodulatorsgivethenewopportunityontheGABABreceptorstargeteddrugdevelopment.Inthisstudy,Imainlystudyontheallostericsmallmoleculecompoundshigh-throughputscreeningoftheGABABreceptorandtheroleofthemolecularmechanisms.Now,AllostericmodulatorsofGABABreceptorareonlyfocusedonfourpositiveallostericagent:CGP7930(2001),GS39783(2003),BHF177(2008),CMPPE(2011).Negativeallostericmodulatorshavenotbeenreported.ShanghaiNationalCenterforDrugScreeningsynthesisavarietyofsmallmoleculecompoundsbasedonthestructureofCGP7930,andthenIconstructCGP7930structure-activityrelationshipmapthroughIP3functiontestingtechnology.AfterelectroporationorliposometransfectionofGB1,GB2andGqi9plasmidstothecelllineHEK293,incubation[3H]myo-inositol,50μMdrugswithdifferentconcentrationGABAst