Investigation of the Structure–Activity Relationships of Psilocybin Analogues 2020 Adam K. Klein.pdf

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InvestigationoftheStructure−ActivityRelationshipsofPsilocybin
Analogues
,MuhammadChatha,,,,
,,*
CiteThis:/
ACCESSMetrics&MoreArticleRecommendations*sıSupportingInformation
ABSTRACT:The5-HT2Areceptoristhoughttobetheprimary
targetforpsilocybin(4-phosphoryloxy-N,N-dimethyltryptamine)
andotherserotonergichallucinogens(psychedelicdrugs).
Althoughalargeamountofexperimentalworkhasbeenconducted
tocharacterizethepharmacologyofpsilocybinandits
dephosphorylatedmetabolitepsilocin(4-hydroxy-N,N-dimethyl-
tryptamine),therehasbeenlittlesystematicinvestigationofthe
structure−activityrelationships(SAR)of4-substitutedtryptamine
,structuralanalogsofpsilocybincontaining
a4-acetoxygroup,suchas4-acetoxy-N,N-dimethyltryptamine(4-
AcO-DMT),haveappearedasnewdesignerdrugs,butalmost

thegapofinformation,studieswereconductedwith17tryptaminescontainingavarietyofsymmetricalandasymmetricalN,N-
dialkylsubstituentsandeithera4-hydroxyor4-
activityathumanandmouse5--twitchresponse(HTR)studieswereconductedinC57BL/6Jmicetoassess5-
-HT2subtypes,displayingsimilarpotenciesat5-
HT2Aand5-HT2Breceptors,butsometryptamineswithbulkierN-alkylgroupshadlowerpotencyat5-HT2Creceptorsandhigher5-
ffi
,O-acetylationreducedtheinvitro5-HT2Apotencyof4-hydroxy-N,N-dialkyltryptaminesby
about10-to20-,consistentwithanLSD-
,acetylationofthe4-hydroxygrouphadlittleeffectonHTRpotency,
suggestingthatO-acetylatedtryptaminesmaybedeacetylatedinvivo,,thetryptaminederivatives
havepsilocybin-likepharmacologicalproperties,supportingtheirclassificationaspsychedelicdrugs.
KEYWORDS:hallucinogen,psychedelicdrug,behavior,functionalassay,serotonin,5-HT2A
,2020at11:35:40(UTC).
silocybin(4-phosphoryloxy-N,N-dimethyltryptamine),,
prototypicalserotonergichallucinogenthatproducesHofmannsynthesized4-hydroxy-N,N-diethyltryptamine(CZ-
Pff
See(LSD)74,4-HO-DET)and4-phosphoryloxy-N,N-diethyltryptamine
andmescaline,isthemajoractiveconstituentofPsilocybe(CEY-19).13Similartopsilocybinandpsilocin,CEY-19and
14,15
mexicanaandotherspeciesofhallucinogenicmushroomsCZ-
(“magicmushrooms”).Psilocybinisrapidlydephosphorylatedsynthesizedseveralotherpsilocinhomologues,including4-
topsilocin(4-hydroxy-N,N-dimethyltryptamine,4-HO-DMT)hydroxy-N-methyl-N-ethyltryptamine(4-HO-MET),4-hy-
−
,5Althoughdroxy-N-methyl-N-isopropyltryptamine(4-HO-MIPT),4-hy-
droxy-N,N-dipropyltryptamine(4-HO-DPT),and4-hydroxy-
psilocybinandpsilocinhaveequivalentmolarpotenciesin16,17
vivo,6psilocybinhasconsiderablylowerpotencyatthereceptorN,N-diisopropyltryptamine(4-HO-DIPT).Tryptamines
level,--
OverthepastdecadetherehasbeenarenewedinterestintheAcetoxy-N,N-dimethyltryptamine(O-acetylpsilocin,4-AcO-
pharmacologyandeffectsofpsilocybinduetoaccumulating
evidencethatitpossessestherapeuticefficacyagainstdisordersSpecialIssue:Psychedelics
suchasanxiety,depression,obsessive-compulsivedisorder,andReceived:October22,2020
,psilocybincontinuestobea
−

Followingtheisolationofpsilocybinandpsilocinby
Hofmannandcolleaguesin1957,12various4-substituted
©XXXXAmericanChemicalSociety/
,XXX,XXX−XXX
ACSPharmacology&
DMT)-Acetoxy-N,N-dimethyltryptamine(4-AcO-DMT)
Shulgin19experimentedwith4-AcO-DMTanditsN,N-diethylfumarate,4-hydroxy-N,N-diethyltryptamine(4-HO-DET)hy-
(4-AcO-DET)andN-methyl-N-isopropyl(4-AcO-MIPT)drochloride,4-acetoxy-N,N-diethyltryptamine(4-AcO-DET)
,4-hydroxy-N-methyl-N-ethyltryptamine(4-HO-
Subsequently,Nicholspublishedanimprovedsynthesisfor4-MET)hemifumarate,4-acetoxy-N-methyl-N-ethyltryptamine
AcO-DMTandproposedthatitcouldserveasanalternative(4-AcO-MET)fumarate,4-hydroxy-N-methyl-N-propyltrypt-
(4-HO-MPT)fumarate,4-acetoxy-N-methyl-N-propyl-
Althoughpsilocinandpsilocybinhavebeenavailableonthetryptamine(4-AcO-MPT)fumarate,4-hydroxy-N-ethyl-N-
illicitmarketsincethe1960s,therecreationaluseofother4-propyltryptamine(4-HO-EPT)3:2fumarate,4-acetoxy-N-
substitutedtryptaminesisamorerecentdevelopment,fueledethyl-N-propyltryptamine(4-AcO-EPT)fumarate,4-hydroxy-
-Acetoxy-N,N-N,N-dipropyltryptamine(4-HO-DPT)hemifumarate,4-ace-
diisopropyltryptamine(4-AcO-DIPT)wasfirstdetectedintoxy-N,N-dipropyltryptamine(4-AcO-DPT)fumarate,4-hy-
Europein2005,21followedby4-AcO-DMT,224-AcO-MET,22droxy-N-methyl-N-isopropyltryptamine(4-HO-MIPT)hemi-
and4-AcO--HO-METand4-HO-DPThavealsofumarate,4-acetoxy-N-methyl-N-isopropyltryptamine(4-AcO-
,23In2011,KjellgranandSoussanpublishedaMIPT)fumarate,4-hydroxy-N,N-diisopropyltryptamine(4-
detaileddescriptionofthephenomenologicaleffectsof4-HO-HO-DIPT)hydrochloride,and4-hydroxy-N-methyl-N-allyl-
,reportsindicatethatmost4-tryptamine(4-HO-MALT)3:2fumaratewereavailablefrom
substitutedtryptaminesproducepsilocybin-likepsychedelic
−-Acetoxy-N,N-
(4-AcO-DIPT)acetatewasobtained
Despitetheincreasingpopularityandavailabilityof4-fromCaymanChemical(AnnArbor,MI).Psilocinwas
acetoxy-N,N-dialkyltryptamines,thereisalackofinformationobtainedfromtheNationalInstituteonDrugAbuse
abouttheirpharmacologicalandbehavioralproperties.(Rockville,MD).Theidentityandanalyticalpurityofthe
Furthermore,althoughnumerousN,N-dialkyltryptaminesfi
−testsubstanceswereconrmedusingmassspectrometryand
havebeenexplored,
investigationoftheeffectofN-alkylsubstitutionontheirhadaminimumpurityof>95%.Forbehavioralstudies,

thegapofknowledgeregardingthestructure−activity(pH∼);allothercompoundsweredissolvedinisotonic
relationships(SARs)
anoxygenatedsubstituentatthe4-positionoftheindolering.(IP)atavolumeof5mL/,all
Wefocusedonactivityatthe5-HT2Areceptor,whichiscompoundsweredissolvedinDMSOat10mMconcentration
thoughttobetheprimarytargetforpsilocybinandotherbeforeserialdilution.
32,33
-
mobilizationassayswereconductedtoassessfunctionalusingahead-mountedneodymiummagnetandamagneto-
35,37
activationathumanandmouse5-HT2A,aswellashuman5-,micewereanesthetized,asmallincision
HT2Band5-,andaneodymiummagnetwasattached
head-twitchresponse(HTR)assaywereusedasameasureoftothedorsalsurfaceofthecraniumusingdentalcement.
34,35
5-,HTRexperimentswere
widelyusedasabehavioralproxyinrodentsforhumancarriedoutinawell-litroomwithatleast7daysbetween
,
thatcanreliablydistinguishhallucinogenicandnonhallucino-miceweretestedinmultipleHTRexperimentsforupto4−5
36
genic5-
with16tryptaminederivativescontainingavarietyoftesting,andthenHTRactivitywasrecordedfor30minina
symmetricalandasymmetricalN,N-.
eithera4-hydroxyora4--pass-filtered(2−10kHzcutoff
invitroandinvivotogenerateconvergingevidenceandtofrequency),amplified,anddigitized(20kHzsamplingrate)
evaluatethelikelihoodthatthe4-acetoxy-N,N-dialkyltrypt-usingaPowerlab/8SPdataacquisitionsystemwithLabChartv
aminesareservingasprodrugsfortheir4-hydroxycounter-(ADInstruments,ColoradoSprings,CO),thenfiltered
-line(40−200Hzband-pass).Headtwitcheswereidentified
basedonthefollowingcriteria:(1)sinusoidalwavelets;(2)
■METHODSevidenceofatleastthreesequentialheadmovements(usually
(6−8weeksold)obtainedexhibitedasbipolarpeaks)withafrequencyof≥40Hz;(3)
fromJacksonLaboratories(BarHarbor,ME)werehousedinaamplitudeexceedingthelevelofbackgroundnoise;(4)
vivariumattheUniversityofCaliforniaSanDiego,anduration<;and(5)stablecoilvoltageimmediately
AAALAC-approvedanimalfacilitythatmeetsallfederalandprecedingandfollowingeachresponse.
staterequirementsforcareandtreatmentoflaboratoryTheentire30minrecordingswereexaminedforhead
-twitches,butinsomeinstances,ashorterblockoftimewas
controlledroomonareverse-lightcycle(lightsonat1900h,usedforanalysistoaccommodatecompoundswitharelatively
offat0700h)-
foodandwater,(ANOVA).Posthocpairwise

werecarriedoutinaccordancewithNIHguidelinesandwereTukey’-
approvedbytheUCSDInstitutionalAnimalCareandUsestratedwhenanα-
fi
(ED50values)and95%condenceintervals(95%CI)
B/
,XXX,XXX−XXX
ACSPharmacology&
forHTRdose−responseexperimentswerecalculatedbysponsecurvesforpsilocinand4-HO-METareshownin
nonlinearregression(,GraphPadSoftware,,somevariation
Diego,CA).
5--HT2functional
experiments(measuringGq-mediatedcalciumflux)were
performedwithFlp-InT-REx293cells(Invitrogen,Carlsbad,
CA)expressingeitherhuman5-HT2A(h5-HT2A),mouse5-
HT2A(m5-HT2A),human5-HT2B(h5-HT2B),orhuman5-
HT2CINI(h5-HT2C)receptorcDNAunderthetetracycline
-wellclear-
bottomedtissuecultureplatesin40μLofDMEMcontaining
1%dialyzedfetalbovineserum(FBS)atadensityof
approximately10000cellsperwell,andreceptorexpression
wasinducedwith2μg/
20−24h,themediumwasdecantedandreplacedwith20μL
perwellofdrugbuffer(HBSS,20mMHEPES,)
containingFluo-4Directdye(Invitrogen)andincubatedfor
between1and2hat37°
drugbuffer(HBSS,20mMHEPES,%bovineserum
albumin,%ascorbicacid,).Beforetheexperiment,
plateswereallowedtoequilibratetoroomtemperature,and
calciumfluxwasmeasuredusingaFLIPRTETRAcellular
screeningsystem(MolecularDevices,Sunnyvale,CA).Plates
werereadforfluorescenceinitiallyfor10s(1readpersecond)
toestablishabaselineandthenstimulatedwithdrugdilutions

eachwellwasnormalizedtothemaximumfoldincreaseover