Thelong-termobjectiveofthisresearchprojectistodevelop?forthefirsttime?competitive antagonists(i.e.reversalagents)forgeneralanesthetics.Thiswouldallowclinicianstoreverseanesthesiaon demandandassistscientistsadvancetheirresearchprograms.Currently,acriticalobstacletodeveloping suchantagonistsforanestheticsthatactviatheGABAAreceptoristhattherearenostrategiesfordesigning competitiveligandsthatcanbindtothereceptor?sanestheticbindingsiteswithoutenhancingthereceptor?s functionandthusproducinganesthesia.Thespecificgoalofthisresearchproposalistoovercomethat obstaclebydiscoveringthefundamentalprinciplesandestablishingthedrugdesignstrategiesthatare necessarytodevelopanestheticcompetitiveantagonistsforclinicalandresearchuse. Wehavediscoveredthatbymodifyingakeyregionofitsmolecularstructure,thehighlyefficacious anestheticetomidatecanbetransformedintoananesthetic-selectivecompetitiveantagonistattheGABAA receptorthatacceleratesinvivoanestheticrecovery.Thisdiscoveryprovidesimportantcluesregardingthe changesthatoccurintheGABAAreceptor?sanestheticbindingsitesasitisomerizesfromclosedtoopen,and suggestsanovelstrategyfordesigninganestheticreversalagentsusingexistinganestheticsasmolecular templates.
Aim1 istobetterunderstandwhysuchmodificationsdramaticallyreduceetomidate?sbinding selectivityfortheopenstateoftheGABAAreceptor,almostcompletelyabolishitsintrinsicefficacyforreceptor activation,andtransformitintoananesthetic-specificcompetitiveantagonistatthereceptor.Itwillalsotest whetheranaloguescontainingthismodificationantagonizethereceptoractionsofotheranestheticsbesides propofolandetomidate.
Aim2 istoquantifythebindingselectivityoftheseetomidateanaloguesforthetwo differentclassesofanestheticbindingsiteslocatedbetweendifferentreceptorsubunitsusingphotoaffinity labelingtechniques.
Aim3 istodefinethebehavioralactionsoftheseanaloguesinratsandtestwhetherone withverylowefficacycanacceleraterecoveryfromhypnosisproducedbydifferentanesthetics. Currently,recoveryfromananesthetic'sactionsmustoccurasapassiveprocesswhosetimecourse isdictatedbytherateofanestheticdrugclearanceratherthantheactualclinicalneed.Theavailabilityof generalanestheticcompetitiveantagonistswouldhaveanenormousimpactonpatientcarebyallowing anestheticemergencetobeactivelymanagedandpreciselycontrolled.Itwouldimprovepatientsafetyand challengecurrentpracticemodelsofanesthesiacarebyallowingpotentiallydeadlysideeffectssuchas respiratorydepressiontobereversedimmediatelyandon-demand.Itwouldalsoadvancescientific researchbyhelpinginvestigatorstolocatenovelsitesofanestheticaction,testforthepossibleexistenceof endogenousligandsforanestheticbindingsites,rationallydesignnewexogenousligandsforthesesites, anddefinetherolethatparticulartargetsplayinproducingvariousinvitroandinvivoanestheticactions.
Theavailabilityofgeneralanestheticcompetitiveantagonistswouldhaveanenormousimpacton patientcarebyallowinganestheticemergencetobeactivelymanagedandpreciselycontrolled.It wouldimprovepatientsafetyandchallengecurrentpracticemodelsofanesthesiacarebyallowing potentiallydeadlysideeffectssuchasrespiratorydepressiontobereversedimmediatelyandon- demand.Thegoalofthisresearchprojectistodiscoverthefundamentalmechanisticprinciplesand establishthedrugdesignstrategiesthatarenecessarytodevelopthisnewclassofdrugs.
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McGrath, Megan; Yu, Zhiyi; Jayakar, Selwyn S et al. (2018) Etomidate and Etomidate Analog Binding and Positive Modulation of ?-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect. Anesthesiology 129:959-969 |
Ma, Celena; Pejo, Ervin; McGrath, Megan et al. (2017) Competitive Antagonism of Anesthetic Action at the ?-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy. Anesthesiology 127:824-837 |