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.

Public Health Relevance

Theavailabilityofgeneralanestheticcompetitiveantagonistswouldhaveanenormousimpacton patientcarebyallowinganestheticemergencetobeactivelymanagedandpreciselycontrolled.It wouldimprovepatientsafetyandchallengecurrentpracticemodelsofanesthesiacarebyallowing potentiallydeadlysideeffectssuchasrespiratorydepressiontobereversedimmediatelyandon- demand.Thegoalofthisresearchprojectistodiscoverthefundamentalmechanisticprinciplesand establishthedrugdesignstrategiesthatarenecessarytodevelopthisnewclassofdrugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM122806-03
Application #
9624776
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2017-04-05
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114