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1、CurrentTopicsinMedicinalChemistry2002,2,903-913903MedicinalChemistryandMolecularPharmacologyofGABACReceptorsGrahamA.R.Johnston*AdrienAlbertLaboratoryofMedicinalChemistry,DepartmentofPharmacology,TheUniversityofSydney,NSW,2006,AustraliaAbstract:GABACreceptorsbelongtothenicotinicoidsuperfamilyofiono
2、tropicreceptorsthatincludenicotinicacetylcholinereceptors,bicuculline-sensitiveGABAAreceptors,strychnine-sensitiveglycinereceptorsand5HT3serotoninreceptors.TheGABACreceptorconceptarosefrommedicinalchemicalstudiesofaconformationallyrestrictedanalogofGABA.ReceptorsmatchingthepredictedpropertiesofGAB
3、ACreceptorswereclonedfromtheretina.Postcloningstudiesrevealedtheuniquephysiologyandpharmacologyoftheserelativelysimplehomomericreceptors.ThreesubtypesofGABACreceptorshavebeenclonedfrommammaliansourcesandpharmaco-logicaldifferencesbetweenther1,r2andr3GABACreceptorshavebeendescribed.Thereisevidencef
4、orfunctionalGABACreceptorsintheretina,spinalcord,superiorcolliculus,pituitaryandthegutandtheirinvolvementinvision,aspectsofmemoryandsleep-wakingbehaviour.ThisreviewconcentratesonthemedicinalchemistryandmolecularpharmacologyofGABACreceptorsubtypesemphasisingpossiblenewinvestigationaltoolswithwhicht
5、oinvestigatefurtherGABACreceptorfunction.ThemostusefulcurrentlyavailableligandsthatshowsomeGABACreceptorsubtypeselectivityareTPMPA,P4PMA,imidazole-4-aceticacid,2-methyl-TACAand(±)-TAMP.KeyWords:GABAreceptors–chloridechannels–CACA–CAMP–TPMPAINTRODUCTIONbicuculline-sensitive,andGABABreceptorsthatwer
6、ebicuculline-insensitiveandactivatedbybaclofen.TheGABAmoleculecanadoptavarietyofdifferentlowenergyconformations.ThedesignanddevelopmentofItisnowknownthatGABAAandGABABreceptorsareGABAanalogsofrestrictedconformationshowedthatfundamentallydifferenttypesofreceptors.GABAAreceptorsdifferentconformations
7、ofGABAwerelikelytointeractareligand-gatedionchannelsmadeupofapentamericwithdifferentmacromoleculesthatrecogniseGABAinitsmixtureofproteinsubunits[4],whileGABABreceptorsarefunctionasaninhibitoryneurotransmitter[1].
