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TheNeuropharmacologyofBenzodiazepinesandDrugswithSimilar
MechanismofAction
RobertB.Raffa,PhDProfessorEmeritus,TempleUniv,PhiladelphiaPAAdjunctProfessor,Univ ArizonaCollegeofPharmacy,TucsonAZNEMAResearchGroup,Naples,FL
TheInternationalBenzodiazepineSymposiumBend,ORSeptember16,2017
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Disclosures
1986– 1996 Johnson&Johnson,analgesicsdrugdiscovery1996– 2016 TempleUniversitySchoolofPharmacy2016– NEMAResearch;CaRafe DrugInnovation(anon-opioid
analgesicsdrugdiscoverycompany);andaconsultant,AdBoard member,speakeronanalgesicsformultiplepharmaceuticalCompanies
Dr.Raffadeclaresnoconflictofinterest– heisnotawareofanydirect,orindirect,benefitfromthesaleofbenzodiazepinesorrelatedtherapy.
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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
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Underlyingprinciples
• TheCNSrequiresbalanceofexcitatoryandinhibitorya.a.• Inbrain:Glu andGABA• Excessexcitation– seizure;excessinhibition– coma
Glu GABA
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Underlyingprinciples
• Anxiety:fearornervousnessaboutwhatmighthappeno productiveforsurvivalo transiento totaleliminationisnotdesirable
• Clinicalanxiety:anabnormal andoverwhelming senseofapprehensionanddread(panic)
o counterproductiveo on-going,physiologicallydrainingo returntobaseline(anxiolysis)desirableo theoptimalapproachmatchesthetreatment(non-
pharmacologicorpharmacologic)tocause
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“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
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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
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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.
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BZDsandotherBZDReceptorAgonists
BZDreceptor-mediatedeffects “Off-target”effects
BZD-Rpharmacology
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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
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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
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BZDMoA:summary
• SelectivebindingtoBZDreceptorsiteonGABAA complex• NoeffectonGABAA bindingsite• PositiveallostericmodulationofGABA-inducedCl– influx• BZDeffectisattenuatedbyBZD-Rantagonist(flumazenil)• BZD-RantagonisthasnodirecteffectonGABA
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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
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https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofBZD-Ragonistbinding
GABA$
Cl– $con
ductance$
Log$[GABA]$
GABA$BZD$
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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
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http://ibmmsrvlakitu.unibe.ch/sigel/video.mp4Middendorp etal.(2014)Chem Biol 9:1854-1859
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Non-BZD-Ragonists
Apharmacophore modelofthebenzodiazepinebindingsiteontheGABAAreceptor.[159]Whitesticksrepresentthecarbonatomsofthebenzodiazepinediazepam,whilegreenrepresentscarbonatomsofthenonbenzodiazepine CGS-9896.Redandbluesticksareoxygenandnitrogenatomsthatarepresentinbothstructures.TheredsphereslabeledH1andH2/A3are,respectively,hydrogenbonddonatingandacceptingsitesinthereceptor,whileL1,L2,andL3denotelipophilicbindingsites.
Samereceptor–>sameeffects(individualdifferencesinPK,off-targetEs)
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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)
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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
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BZD-Rinhumanbrain
Receptorautoradiographyusing[3H]Flunitrazepam1
• Highestdensitieslocalizedincorticalandlimbicregions(hippocampus,nu.accumbens,amygdala,andmammillarybodies)
• Intermediatedensitiesinbasalgangliaandthalamicandhypothalamicnuclei
• Lowdensitiesinbrainstem• Verylowdensitiesinwhitematter
1Zezulaetal.(1988)Neuroscience.25:771-795.
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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
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MultipleGABA-Areceptors
• 6differentαsubunits• 4differentβsubunits• 3differentγ subunits• mostcommonmammalian:(α1)2(β2)2(γ2)1
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Neuronalsystemeffects
Inhibition Governor Disinhibition
inhibitoryexcitatory
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sedation –– Beneficial calming–– Also used to denote an AE
anxiolytic –– Reduces anxiety without impairment of alertness
hypnotic –– Produces drowsiness and (normal) sleep
Anxiolyticeffect
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‘Normal’anxiety• normalresponseof‘fightorflight’• normallyresolvesw/omedication• but,sensitizationtorepeatedstresscandisrupt
normalphysiology
‘Clinical’anxiety• panicattacks,phobias,OCD,possiblyPTSD• clinicallysignificantin~10%ofthepopulation• endogenouscause,orconsequence
Anxiolyticeffect
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• majorinhibitoryNTinCNS(primarilybrain)• balancewithexcitatoryaminoacids• NTatabout30%ofallCNSsynapses• allCNSneuronsandglialcellsaresensitivetoGABA
GABA
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• 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
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AEsofBZDslessthanthoseofbarbiturates:• CNSdepression• respiratorydepression• psychomotorfunction• daytimesleepiness• effectsonREMsleep• EtOH interaction• hepaticenzymeinduction• DDIs
Placeintherapeutichistory
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BZDADME:A,DandE
• mostarereadilyabsorbedfromGItract• drug-specificextentof1st-passeffect• availableinmultipledosageforms• manyarelipidsoluble
o passBBBo mostreadilypassplacentao redistributionto/fromfattytissueo extendeddurationofeffect
• mostBZDsareeliminatedvia urinaryexcretion
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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
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• 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)
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DDIs:PK– metabolic
https://upload.wikimedia.org/wikipedia/commons/9/98/PropDrugsMetabCYP.png
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Adverseeffects
Glu GABA
BZD
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Tolerance
• Normalphysiologicprocess• Developstomostdrugs• Candevelopatdifferentratesfordifferenteffects
Ø TIcandecreasewithtreatmentduration
Dose
Effect
Dose
Effect
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Physicaldependence/withdrawal
• Physicaldependenceisanormalphysiologicprocess• Developstomostdrugs• Usuallycompensatoryoppositetodrug-inducedeffect• Revealedduringwithdrawal(unopposed)• MostseriousforBZDsisexcessexcitation
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• 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
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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
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Recap
1. Perspectiveonanxietyandanxiolysis2. Developafundamentalandworkingknowledgeofthe
targetandmechanismofBZDanxiolyticactivityu reviewtheassociationanddifferencebetweenGABAA andBZD
receptorsu developanunderstandingofwhyBZDand‘Z,E’drugssharea
commonanxiolyticmechanism3. Reviewbasicneuropharmacol ofBZDandrelateddrugs4. DiscusssomeADMEfeaturesofthesedrugs5. Broadlydiscuss‘peripheral’BZDreceptors