the neuropharmacology of benzodiazepines and drugs with … · 2019. 1. 24. · objectives...
TRANSCRIPT
![Page 1: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/1.jpg)
TheNeuropharmacologyofBenzodiazepinesandDrugswithSimilar
MechanismofAction
RobertB.Raffa,PhDProfessorEmeritus,TempleUniv,PhiladelphiaPAAdjunctProfessor,Univ ArizonaCollegeofPharmacy,TucsonAZNEMAResearchGroup,Naples,FL
TheInternationalBenzodiazepineSymposiumBend,ORSeptember16,2017
![Page 2: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/2.jpg)
Disclosures
1986– 1996 Johnson&Johnson,analgesicsdrugdiscovery1996– 2016 TempleUniversitySchoolofPharmacy2016– NEMAResearch;CaRafe DrugInnovation(anon-opioid
analgesicsdrugdiscoverycompany);andaconsultant,AdBoard member,speakeronanalgesicsformultiplepharmaceuticalCompanies
Dr.Raffadeclaresnoconflictofinterest– heisnotawareofanydirect,orindirect,benefitfromthesaleofbenzodiazepinesorrelatedtherapy.
![Page 3: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/3.jpg)
Objectives
1. Describethebasicneurophysiologyofanxietyandanxiolysis2. DevelopthetargetandmechanismofBZDanxiolyticactivity
u describetheassociationanddifferencebetweenGABAA andBZDreceptors
u describewhyBZDand‘Z,E’drugsshareacommonanxiolyticmechanism
3. DescribethebasicneuropharmacologyofBZDandrelateddrugs
4. DescribebasicADME(absorption,distribution,metabolism,elimination)featuresofthesedrugs
5. Describe‘peripheral’BZDreceptors
![Page 4: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/4.jpg)
Underlyingprinciples
• TheCNSrequiresbalanceofexcitatoryandinhibitorya.a.• Inbrain:Glu andGABA• Excessexcitation– seizure;excessinhibition– coma
Glu GABA
![Page 5: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/5.jpg)
Underlyingprinciples
• Anxiety:fearornervousnessaboutwhatmighthappeno productiveforsurvivalo transiento totaleliminationisnotdesirable
• Clinicalanxiety:anabnormal andoverwhelming senseofapprehensionanddread(panic)
o counterproductiveo on-going,physiologicallydrainingo returntobaseline(anxiolysis)desirableo theoptimalapproachmatchesthetreatment(non-
pharmacologicorpharmacologic)tocause
![Page 6: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/6.jpg)
“Benzodiazepine”pharmacology
• Benzodiazepines(BZDs)aredefinedbasedonchemicalstructure(benzenze ringplusdiazepine ring)
• Benzodiazepines(BZDs)producetheirmajoreffectsthrough affinityfor(bindingto)andintrinsicactivity(agonistaction)atbenzodiazepinereceptors(BZD-R)
• Butsubstanceswithnon-benzodiazepinechemicalstructures(e.g.,the“Z”drugs)alsoactatBZD-R
• èThepharmacologiceffectsarethesame• Thus,itismostinformativetospeakofBZD-Rpharmacology
![Page 7: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/7.jpg)
β-Carbolines:Abecarnil,Gedocarnil,SL-651,498,ZK-93423
Others:CGS-20625,CGS-9896,CL-218,872,ELB-139,GBLD-345,L-838,417,NS-2664,NS-2710,Pipequaline,RWJ-51204,SB-205,384,SL-651,498,SX-3228,TP-003,TP-13,TPA-023,Y-23684
N
N
N
N
N
N N N
N
NN
O
OH
BenzodiazepinesImidazopyridines Pyrazolopyrimidines Cyclopyrrolonese.g.,Zolpidem(AMBIEN,etc.)
e.g.,Zaleplon(SONATA,etc.)
e.g.,Eszopiclone(LUNESTA,etc.)Zopiclone(IMOVANE,etc.)
Non-BZDBZD-Ragonists
![Page 8: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/8.jpg)
CentralBZDreceptors• discoveredin19771• autoradiographic demonstrationinhumanbrainin19882• positiveallostericmodulationoftheGABA-Areceptor
PeripheralBZDreceptors• discoveredin19923• Tryptophan-richsensoryprotein(TspO)
(translocator protein)
BZD-Rpharmacology
1MöhlerandOkada(1977)Science198:849-851; SquiresandBraestrup (1977)Nature266:732-734.2Zezulaetal.(1988)Neuroscience25:771-795.3McEneryetal.(1992)PNAS89:3170-3174.
![Page 9: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/9.jpg)
BZDsandotherBZDReceptorAgonists
BZDreceptor-mediatedeffects “Off-target”effects
BZD-Rpharmacology
![Page 10: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/10.jpg)
https://upload.wikimedia.org/wikipedia/commons/4/46/NAchR_2BG9.pnghttps://upload.wikimedia.org/wikipedia/commons/0/06/GABAA_receptor_schematic.png
GABAA ionotropic receptor
![Page 11: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/11.jpg)
https://upload.wikimedia.org/wikipedia/commons/4/46/NAchR_2BG9.pnghttps://commons.wikimedia.org/wiki/File:GABAA-receptor-protein-example.pnghttps://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
CentralBZDreceptor
GABABZD
![Page 12: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/12.jpg)
BZDMoA:summary
• SelectivebindingtoBZDreceptorsiteonGABAA complex• NoeffectonGABAA bindingsite• PositiveallostericmodulationofGABA-inducedCl– influx• BZDeffectisattenuatedbyBZD-Rantagonist(flumazenil)• BZD-RantagonisthasnodirecteffectonGABA
![Page 13: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/13.jpg)
0""
mV""
–60""
–70""
–80" Time""
Threshold ReTrPotlΔ
E " " " """""E"I"
GABA$BZD$
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofGABAA agonistbinding
![Page 14: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/14.jpg)
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofBZD-Ragonistbinding
GABA$
Cl– $con
ductance$
Log$[GABA]$
GABA$BZD$
![Page 15: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/15.jpg)
GABA$BZD$
0""
mV""
–60""
–70""
–80" Time""
Threshold ReTrPotlΔ
E " " " """""E"I"
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofBZD-Rantagonistbinding
![Page 16: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/16.jpg)
http://ibmmsrvlakitu.unibe.ch/sigel/video.mp4Middendorp etal.(2014)Chem Biol 9:1854-1859
![Page 17: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/17.jpg)
Non-BZD-Ragonists
Apharmacophore modelofthebenzodiazepinebindingsiteontheGABAAreceptor.[159]Whitesticksrepresentthecarbonatomsofthebenzodiazepinediazepam,whilegreenrepresentscarbonatomsofthenonbenzodiazepine CGS-9896.Redandbluesticksareoxygenandnitrogenatomsthatarepresentinbothstructures.TheredsphereslabeledH1andH2/A3are,respectively,hydrogenbonddonatingandacceptingsitesinthereceptor,whileL1,L2,andL3denotelipophilicbindingsites.
Samereceptor–>sameeffects(individualdifferencesinPK,off-targetEs)
![Page 18: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/18.jpg)
BZD-R:phylogenetically old
KristinFinno,TUundergrad;TJUPharmacy
0102030405060708090
100110120130140150160170
0 1 2 3 4 5 6 7 8 9 1011
LMA
(grid
lines
cro
ssed
)
Time (min)
![Page 19: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/19.jpg)
BZD-Rinplanarians
• BZDs(clorazepate,midazolam)producedose-relatedeffects(alterbehavior)
• TheBZD-inducedeffectsaredose-relatedlyattenuatedbyaBZD-R-selectiveantagonist(flumazenil)
• Thenon-BZDBZD-Ragonist(zolpidem)dose-relatedlyproducesthesameeffectsastheBZDs
• Thenon-BZD-inducedeffectsareattenuatedbyaBZD-R-selectiveantagonist(flumazenil)
Raffaetal.(2007)Eur JPharmacol 564:88-93
![Page 20: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/20.jpg)
BZD-Rinhumanbrain
Receptorautoradiographyusing[3H]Flunitrazepam1
• Highestdensitieslocalizedincorticalandlimbicregions(hippocampus,nu.accumbens,amygdala,andmammillarybodies)
• Intermediatedensitiesinbasalgangliaandthalamicandhypothalamicnuclei
• Lowdensitiesinbrainstem• Verylowdensitiesinwhitematter
1Zezulaetal.(1988)Neuroscience.25:771-795.
![Page 21: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/21.jpg)
WhyaBZD-R?
IsthereanendogenousBZD-Ragonist?anendozepine?thebrain’sValium?
• flumazinil doesnotbindtoGABAA-R,butcaninducepanicattacksinpatientswithpanicdisorder(butnothealthycontrols)
• BZDsarefoundinbraintissue– butalsoinplants• oleamides,inosine,hypoxanthine,nicotimide:onlylowaffinityfor
BZD-R;DBI(diazepam-bindinginhibitor)actuallyacyl-CoA-bindingprotein
• thequestionremainsunanswered
Farzampour etal.(2015)Adv Pharmacol 72:147-164
![Page 22: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/22.jpg)
MultipleGABA-Areceptors
• 6differentαsubunits• 4differentβsubunits• 3differentγ subunits• mostcommonmammalian:(α1)2(β2)2(γ2)1
![Page 23: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/23.jpg)
Neuronalsystemeffects
Inhibition Governor Disinhibition
inhibitoryexcitatory
![Page 24: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/24.jpg)
sedation –– Beneficial calming–– Also used to denote an AE
anxiolytic –– Reduces anxiety without impairment of alertness
hypnotic –– Produces drowsiness and (normal) sleep
Anxiolyticeffect
![Page 25: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/25.jpg)
‘Normal’anxiety• normalresponseof‘fightorflight’• normallyresolvesw/omedication• but,sensitizationtorepeatedstresscandisrupt
normalphysiology
‘Clinical’anxiety• panicattacks,phobias,OCD,possiblyPTSD• clinicallysignificantin~10%ofthepopulation• endogenouscause,orconsequence
Anxiolyticeffect
![Page 26: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/26.jpg)
• majorinhibitoryNTinCNS(primarilybrain)• balancewithexcitatoryaminoacids• NTatabout30%ofallCNSsynapses• allCNSneuronsandglialcellsaresensitivetoGABA
GABA
![Page 27: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/27.jpg)
• Psychotherapeutic,cognitive,behavioral,and• Pharmacologic(onlyifappropriate)
o acuteattackso chronicuse=4-8weekso BZDsbetterTE/AEratiothanbarbiturates
o newerdrugshavebetterTE/AEratiothanBZDs
More specific to anxiety & Fewer AE�s
Placeintherapeutichistory
barbiturates, ethanolDeath
Coma
Anesthesia
Hypnosis
Sedation
DOSE
benzodiazepines
![Page 28: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/28.jpg)
AEsofBZDslessthanthoseofbarbiturates:• CNSdepression• respiratorydepression• psychomotorfunction• daytimesleepiness• effectsonREMsleep• EtOH interaction• hepaticenzymeinduction• DDIs
Placeintherapeutichistory
![Page 29: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/29.jpg)
BZDADME:A,DandE
• mostarereadilyabsorbedfromGItract• drug-specificextentof1st-passeffect• availableinmultipledosageforms• manyarelipidsoluble
o passBBBo mostreadilypassplacentao redistributionto/fromfattytissueo extendeddurationofeffect
• mostBZDsareeliminatedvia urinaryexcretion
![Page 30: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/30.jpg)
BZDADME:metabolism
• hepaticvia Phase1(CYP450andother)andPhase2(glucuronide conjugation),commonlyinsequenceandparallel
• manyPhase1BZDmetabolitesactive(clorazepate aprodrug tooxazepam)
• oxazepam isalsoametaboliteofchlordiazepoxide,diazepam,andprazepam
• alprazolam,flurazepam,lorazepam,triazolam:directglucuronidation
• eszopiclone andzolpidem viaCYP3A4• zaleplon via aldehydeoxidase
![Page 31: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/31.jpg)
• ethanol,barbiturates,andneurosteroids• additiveorsupra-additiveCNSdepression
DDIs:PD– otherGABAA-Rmodulators
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
GABABZD
EtOH (α)barbiturates(β)propofol (β)neurosteroids (β)
![Page 32: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/32.jpg)
DDIs:PK– metabolic
https://upload.wikimedia.org/wikipedia/commons/9/98/PropDrugsMetabCYP.png
![Page 33: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/33.jpg)
Adverseeffects
Glu GABA
BZD
![Page 34: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/34.jpg)
Tolerance
• Normalphysiologicprocess• Developstomostdrugs• Candevelopatdifferentratesfordifferenteffects
Ø TIcandecreasewithtreatmentduration
Dose
Effect
Dose
Effect
![Page 35: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/35.jpg)
Physicaldependence/withdrawal
• Physicaldependenceisanormalphysiologicprocess• Developstomostdrugs• Usuallycompensatoryoppositetodrug-inducedeffect• Revealedduringwithdrawal(unopposed)• MostseriousforBZDsisexcessexcitation
![Page 36: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/36.jpg)
• BZDsalsobindtootherreceptors,locatedmainlyinperipheraltissuesandglialcellsinthebrain
• Originallytermed‘peripheralBZD-R’,alsoknownastranslocator protein(TSPO)
• Functionsnotfullyknown,butmightinvolvesteroidbiochemistry/transport,cellproliferation/apoptosis,andimmunomodulation
• TSPOnull(Tspo–/–)miceareviable1
1Tuetal.(2014)JBiol Chem 289:27444-27454
OtherBZDbindingsites
![Page 37: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/37.jpg)
PeripheralBZD /TSPOdistribution
• 6healthycontrolsubjects (3men,3women)• 11C-DPA-713,aspecificPETligandfortheassessmentofTSPO• whole-bodyPET/CT(PositronEmissionTomography– ComputedTomography)• absorbeddosehighestinthelungs,spleen,kidney,andpancreas
Radia%on(Dosimetry(and(Biodistribu%on(of(the(TSPO(Ligand(11C=DPA=713(in(Humans(Endres(et#al.#(2012)(J(Nuclear(Med(53:330=335((
http://jnm.snmjournals.org/content/53/2/330
![Page 38: The Neuropharmacology of Benzodiazepines and Drugs with … · 2019. 1. 24. · Objectives 1.Describe the basic neurophysiology of anxiety and anxiolysis 2.Develop the target and](https://reader034.vdocuments.us/reader034/viewer/2022051907/5ffa7717ac4f5342bd2a1a7e/html5/thumbnails/38.jpg)
Recap
1. Perspectiveonanxietyandanxiolysis2. Developafundamentalandworkingknowledgeofthe
targetandmechanismofBZDanxiolyticactivityu reviewtheassociationanddifferencebetweenGABAA andBZD
receptorsu developanunderstandingofwhyBZDand‘Z,E’drugssharea
commonanxiolyticmechanism3. Reviewbasicneuropharmacol ofBZDandrelateddrugs4. DiscusssomeADMEfeaturesofthesedrugs5. Broadlydiscuss‘peripheral’BZDreceptors