the neuropharmacology of benzodiazepines and drugs with … · 2019. 1. 24. · objectives...

TheNeuropharmacologyofBenzodiazepinesandDrugswithSimilar

MechanismofAction

RobertB.Raffa,PhDProfessorEmeritus,TempleUniv,PhiladelphiaPAAdjunctProfessor,Univ ArizonaCollegeofPharmacy,TucsonAZNEMAResearchGroup,Naples,FL

TheInternationalBenzodiazepineSymposiumBend,ORSeptember16,2017

Disclosures

1986– 1996 Johnson&Johnson,analgesicsdrugdiscovery1996– 2016 TempleUniversitySchoolofPharmacy2016– NEMAResearch;CaRafe DrugInnovation(anon-opioid

analgesicsdrugdiscoverycompany);andaconsultant,AdBoard member,speakeronanalgesicsformultiplepharmaceuticalCompanies

Dr.Raffadeclaresnoconflictofinterest– heisnotawareofanydirect,orindirect,benefitfromthesaleofbenzodiazepinesorrelatedtherapy.

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

Underlyingprinciples

• TheCNSrequiresbalanceofexcitatoryandinhibitorya.a.• Inbrain:Glu andGABA• Excessexcitation– seizure;excessinhibition– coma

Glu GABA

Underlyingprinciples

• Anxiety:fearornervousnessaboutwhatmighthappeno productiveforsurvivalo transiento totaleliminationisnotdesirable

• Clinicalanxiety:anabnormal andoverwhelming senseofapprehensionanddread(panic)

o counterproductiveo on-going,physiologicallydrainingo returntobaseline(anxiolysis)desirableo theoptimalapproachmatchesthetreatment(non-

pharmacologicorpharmacologic)tocause

“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

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

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.

BZDsandotherBZDReceptorAgonists

BZDreceptor-mediatedeffects “Off-target”effects

BZD-Rpharmacology

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

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

BZDMoA:summary

• SelectivebindingtoBZDreceptorsiteonGABAA complex• NoeffectonGABAA bindingsite• PositiveallostericmodulationofGABA-inducedCl– influx• BZDeffectisattenuatedbyBZD-Rantagonist(flumazenil)• BZD-RantagonisthasnodirecteffectonGABA

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

https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png

EffectofBZD-Ragonistbinding

GABA$

Cl– $con

ductance$

Log$[GABA]$

GABA$BZD$

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

http://ibmmsrvlakitu.unibe.ch/sigel/video.mp4Middendorp etal.(2014)Chem Biol 9:1854-1859

Non-BZD-Ragonists

Apharmacophore modelofthebenzodiazepinebindingsiteontheGABAAreceptor.[159]Whitesticksrepresentthecarbonatomsofthebenzodiazepinediazepam,whilegreenrepresentscarbonatomsofthenonbenzodiazepine CGS-9896.Redandbluesticksareoxygenandnitrogenatomsthatarepresentinbothstructures.TheredsphereslabeledH1andH2/A3are,respectively,hydrogenbonddonatingandacceptingsitesinthereceptor,whileL1,L2,andL3denotelipophilicbindingsites.

Samereceptor–>sameeffects(individualdifferencesinPK,off-targetEs)

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)

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

BZD-Rinhumanbrain

Receptorautoradiographyusing[3H]Flunitrazepam1

• Highestdensitieslocalizedincorticalandlimbicregions(hippocampus,nu.accumbens,amygdala,andmammillarybodies)

• Intermediatedensitiesinbasalgangliaandthalamicandhypothalamicnuclei

• Lowdensitiesinbrainstem• Verylowdensitiesinwhitematter

1Zezulaetal.(1988)Neuroscience.25:771-795.

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

MultipleGABA-Areceptors

• 6differentαsubunits• 4differentβsubunits• 3differentγ subunits• mostcommonmammalian:(α1)2(β2)2(γ2)1

Neuronalsystemeffects

Inhibition Governor Disinhibition

inhibitoryexcitatory

sedation –– Beneficial calming–– Also used to denote an AE

anxiolytic –– Reduces anxiety without impairment of alertness

hypnotic –– Produces drowsiness and (normal) sleep

Anxiolyticeffect

‘Normal’anxiety• normalresponseof‘fightorflight’• normallyresolvesw/omedication• but,sensitizationtorepeatedstresscandisrupt

normalphysiology

‘Clinical’anxiety• panicattacks,phobias,OCD,possiblyPTSD• clinicallysignificantin~10%ofthepopulation• endogenouscause,orconsequence

Anxiolyticeffect

• majorinhibitoryNTinCNS(primarilybrain)• balancewithexcitatoryaminoacids• NTatabout30%ofallCNSsynapses• allCNSneuronsandglialcellsaresensitivetoGABA

GABA

• 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

AEsofBZDslessthanthoseofbarbiturates:• CNSdepression• respiratorydepression• psychomotorfunction• daytimesleepiness• effectsonREMsleep• EtOH interaction• hepaticenzymeinduction• DDIs

Placeintherapeutichistory

BZDADME:A,DandE

• mostarereadilyabsorbedfromGItract• drug-specificextentof1st-passeffect• availableinmultipledosageforms• manyarelipidsoluble

o passBBBo mostreadilypassplacentao redistributionto/fromfattytissueo extendeddurationofeffect

• mostBZDsareeliminatedvia urinaryexcretion

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

• 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)

DDIs:PK– metabolic

https://upload.wikimedia.org/wikipedia/commons/9/98/PropDrugsMetabCYP.png

Adverseeffects

Glu GABA

BZD

Tolerance

• Normalphysiologicprocess• Developstomostdrugs• Candevelopatdifferentratesfordifferenteffects

Ø TIcandecreasewithtreatmentduration

Dose

Effect

Dose

Effect

Physicaldependence/withdrawal

• Physicaldependenceisanormalphysiologicprocess• Developstomostdrugs• Usuallycompensatoryoppositetodrug-inducedeffect• Revealedduringwithdrawal(unopposed)• MostseriousforBZDsisexcessexcitation

• 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

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

Recap

1. Perspectiveonanxietyandanxiolysis2. Developafundamentalandworkingknowledgeofthe

targetandmechanismofBZDanxiolyticactivityu reviewtheassociationanddifferencebetweenGABAA andBZD

receptorsu developanunderstandingofwhyBZDand‘Z,E’drugssharea

commonanxiolyticmechanism3. Reviewbasicneuropharmacol ofBZDandrelateddrugs4. DiscusssomeADMEfeaturesofthesedrugs5. Broadlydiscuss‘peripheral’BZDreceptors

robert.raffa@gmail.com