BLOCKING
`
`INHIBITORY
`OF
`DICHLORO
`ANALOG
`
`RECEPTORS
`ADRENEI{GIC
`OF
`ISOPROTERENOL’
`
`BY
`
`A
`
`799,7
`
`C. E.
`
`POWELL
`
`AND
`
`I. H.
`
`SLATER
`
`With
`
`technical
`
`assistance
`
`of Lester
`
`LeCompte,
`
`Jr.
`
`and
`
`James
`
`E. Waddell
`
`Lilly
`
`Research
`
`Laboratories,
`
`Eli
`
`Lilly
`
`and
`
`Company,
`
`indianapolis
`
`6,
`
`Indiana
`
`lteceive(l
`
`for
`
`publication
`
`December
`
`21,
`
`1957
`
`I)urimig
`
`amnines,
`
`investigatiomi
`ami
`it was
`
`observed
`
`of
`
`that
`
`a series
`1 -(3’
`
`selectively
`
`blocked
`
`hydrochloride
`and
`isoproterenol.
`amities
`mimetic
`of
`antagonism
`found
`that
`uterus,
`and
`following
`isolated
`
`and
`phenethyl-
`chlorinated
`of
`, 4’-dichlorophenyl)-2-isopropylaininoet.hanol
`some
`of
`the
`inhibitory
`actions
`
`phenethanol-
`
`of
`
`epinephrine
`
`effects
`only
`
`ca.t
`
`of
`
`the
`by
`
`has
`of
`ephedrine
`that
`after
`year
`Finkleman
`rabbit
`intestine
`test
`
`as
`
`the
`
`sixteen
`
`intestine
`
`Although
`been
`often
`t.he
`inhibitory
`contracted
`ephedrine,
`observed
`could
`be
`organ,
`Astrom
`phenethyl
`members,
`were,
`however,
`perfused
`isolated
`that
`some
`
`amines.
`blocked
`pressor
`guinea
`sympathomimetic
`
`of
`a
`series
`of
`phenyl-substituted
`These
`compounds
`In
`a
`study
`on
`(1951)
`also
`
`noted
`
`blockade
`reported
`effects
`isolated
`epinephrine
`that
`blocked
`(1949)
`All
`the
`amines
`pig
`lung,
`
`of
`
`excitatory
`the
`of
`(Nickerson,
`have
`been
`strips
`failed
`relaxing
`ephedrine.
`the
`studied
`compounds,
`the
`action
`inhibitory
`varying
`with
`Neidle,
`amines
`
`sympatho-
`of
`a few examples
`1949),
`published.
`In
`1929,
`Curtis
`and
`guinea
`pig
`both
`these
`organs.
`The
`to
`relax
`of
`epimiephrine
`on
`action
`using
`isolated
`Also
`antisympathetic
`except
`
`rabbit
`action
`dihydroxy-
`
`of.
`degrees
`Gruber
`capable
`
`were
`
`epinephrine.
`of potency.
`Copeland
`blocking
`
`of
`
`and
`
`of
`
`the
`
`action
`bronchodilator
`Dichlorophemiyl-2-isopropylaminoethanol
`agents
`by
`showing
`relatively
`excitatory
`action.
`The
`following
`of
`this
`analog.
`
`epinephrine.
`
`weak
`
`differs
`effects
`
`inhibitory
`report
`described
`
`from
`and
`certain
`
`previously
`the
`virtually
`being
`pharmacological
`
`reported
`devoid
`actions
`
`of
`
`The
`hydrochloride
`METHODS.
`is a white
`crystalline
`Lilly
`20522,
`a sense
`the
`dichloro
`analog
`It
`is
`in
`tural
`formula
`as
`follows’:
`
`is
`
`1 -(3’,
`4’
`of
`salt
`readily
`substance
`of
`isoproterenol
`
`dichlorophenyl)-2-isopropylaminoethaniol,
`soluble
`in water
`at
`room
`(isopropylnorepinephrine).
`
`temperature.
`The
`struc(cid:1)
`
`HH
`0
`
`Cl
`
`-C-C-NH-CHHC1.
`
`Cl-/
`
`HH
`
`CH(cid:1)
`
`CH
`
`Presented
`
`in
`
`part
`
`at
`
`the
`
`Federation
`
`of American
`
`Societies
`
`for
`
`Experimental
`
`Biology
`
`Illinois, 1957.
`Chicago,
`was
`2 This compound
`
`and
`
`Company.
`
`synthesized
`
`by Dr.
`
`J. Mills, Organic
`
`Chemistry
`
`Division,
`
`Eli Lilly
`
`480
`
`AstraZeneca Exhibit 2088
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 9
`
`(cid:1)
`

`
`1958
`
`INHIBITORY
`
`AI)1tENERGIC
`
`BLOCKADE
`
`481
`
`Blood
`recorded
`a gravity
`
`twelve
`of
`pressure
`a mercury
`hV
`writing
`lever
`
`(cid:1)vai(
`vith
`
`anesthetized
`cats,
`six
`In
`manometer.
`attached
`a string
`
`by
`
`with
`female
`to
`
`50 mgnn./kgm.
`cats,
`uterine
`the mi(lpoint
`
`chloralose
`of
`motility
`was
`of one
`uterine
`
`vein.
`by
`recorded
`horn.
`The
`
`anchored
`were
`horn
`of
`ends
`two
`in two
`rotameter
`a Shipley-Wilson
`rotameter
`The
`iv.).
`mgm./kgm.,
`leg with
`hind
`right
`artery
`artery
`femoral
`the
`injected
`in
`prepared
`were
`in
`this
`isolated
`5 strips
`of
`on
`determined
`isolated
`muscles
`The
`from 3 rats.
`maintained
`at
`Tyrode
`solution
`intrapulmonary
`Changes
`of
`pithed
`dogs
`by the method
`by
`exerting
`negative
`pressure
`air
`thoracic
`The
`cage.
`flow
`nected
`arm.
`a side
`Guinea
`pig
`tracheal
`(1947).
`Preparations
`counter-balanced
`maintained
`aerated
`medium.
`epinephrine
`induced
`
`the
`
`of
`
`the
`into
`study
`
`to
`
`Blood
`holder.
`organ
`to a glass
`flow
`sodium
`with
`anesthetized
`female
`(logs
`the
`divided
`was
`between
`attached
`supply
`remaining
`venous
`nerve
`and
`Isolated
`frog
`rotameter.
`to the
`smooth
`nuiscle
`usual
`manner.
`The
`intestine
`from
`3 rabbits
`4 strips
`and
`were
`suspended
`a constant
`temnperature
`37.5#{176}C.
`resistance
`Jackson
`on
`a
`through
`
`the
`distal
`the
`
`with
`(letermined
`was
`(150
`phenobarhital
`femoral
`ends
`of
`the
`intact.
`I)rugs
`were
`hearts
`(Straub)
`used
`action
`of 20522
`was
`of
`isolated
`uterus
`bath
`containing
`
`in
`ventilation
`was
`from
`
`nine
`
`placed
`a
`
`decerebrate-
`achieved
`was
`inside
`the
`tambour
`con
`
`iti
`
`were
`air
`to
`flow
`this
`(1939). With
`\(cid:1)‘ocher
`plethysmograph
`a
`tracheal
`cannula
`
`was
`
`determined
`method,
`which
`estimated
`
`of
`
`prepared
`were
`chains
`a
`in
`suspended
`were
`a 15-fold
`having
`lever
`heart
`containing
`solution
`37.5#{176}C.Ringer
`with
`5 per
`95
`per
`cent
`oxygen
`and
`cent
`Pilocarpine
`added
`in a concentration
`was
`were
`recorded
`on
`smoked
`20522
`and
`had
`reached
`a stable
`plateau.
`
`at
`
`spa.sm
`
`to the method
`according
`muscle
`chamber
`100-mI.
`magnification.
`Temperature
`twice
`usual
`amount
`the
`carbon
`dioxide
`was
`imsed
`of
`1 mgm.
`100 ml.
`kymograph
`after
`
`deBeer
`and
`of Castillo
`to
`and
`connected
`was
`bath
`of
`the
`and
`of
`dextrose
`bathing
`as
`the
`The
`responses
`the
`pilocarpine-
`
`a
`
`to
`
`per
`paper
`
`RESULTS.
`
`imi doses
`pressure
`
`12
`
`cats
`
`anesthetized
`
`with
`
`intravenously,
`
`of
`series
`a
`10 mgm./kgm.
`observable
`rate
`of
`of
`
`change.
`injection,
`blood
`change.
`no
`blood
`
`for
`pressure,
`The
`pressure
`i.v.
`of
`
`The
`after
`
`in
`
`of
`to
`
`2,
`
`of
`
`in
`
`to
`
`the
`
`20522,
`chloralose,
`In
`blood
`fall
`either
`caused
`of 5 to
`to
`seemed
`blood
`of
`degree
`or
`no
`usually
`was
`administration
`rapid
`the
`to
`related
`injection
`cases
`other
`whereas
`lowering
`definite
`amities
`sympathomimet.ic
`of
`various
`effect
`with
`associated
`to
`returned
`had
`t.he
`after
`tested
`shown
`As
`a
`steady
`secondary
`blocked
`20522
`compound
`1,
`figure
`only
`5 mgm./kgm.
`the
`had
`effect
`of epinephrine,
`pressor
`to
`epinephrine
`response
`pressor
`effect
`no
`on
`the
`depressor
`considerably
`decreased
`and
`or
`levarterenol
`(norepinephrine),
`10 mgm./kgm.
`of
`seemed
`to
`there
`doses
`after
`effect
`isoproterenol.
`However,
`and
`almost
`responses
`pressor
`levarterenol
`and
`enhancement
`of
`epinephrine
`animals
`the
`In
`other
`isoproterenol.
`response
`to
`complete
`the
`depressor
`block
`10 mgm./kgm.
`5 and
`after
`unchanged
`pressor
`carot.id
`occlusion
`response
`was
`membrane
`nictitating
`t.he
`of
`contraction
`doses
`20522.
`Similarly,
`compound
`change.
`did
`not
`stimulation
`induced
`epinephrine
`or
`preganglionic
`by
`either
`remained
`unchamiged.
`depressor
`to
`either
`histamine
`or methacholine
`response
`followed
`rapid
`injection
`a
`a transient
`fall
`in blood
`shown
`pressure
`figure
`uterine
`movements
`were
`compound
`(5.0 mgm./kgm.,
`The
`normal
`20522
`i.v.).
`level,
`altered.
`after
`recovery
`to
`preinject.ion
`However,
`the
`pressor
`response
`relaxation
`uterine
`previously
`slightly
`enhanced
`amid
`the
`was
`epinephrimie
`the
`countered
`inhibited
`in all
`of
`6 cats
`tested.
`A slight reversal
`of
`the
`was
`observed
`in 2 of
`In
`all
`experiments
`response
`epinephrimie
`6 cat.s
`tested.
`was
`depressor
`action
`and
`uterine
`relaxing
`activity
`of
`isoproterenol
`were
`
`a
`pressure
`
`compound
`transient
`fall
`there
`slow
`
`in
`
`level.
`the
`
`be
`a
`
`was
`
`was
`
`in
`de-
`
`be
`
`The
`As
`of
`not
`to
`en-
`uterine
`t.he
`blocked
`
`Page 2 of 9
`
`

`
`482
`
`Po\vaLm.
`
`.(cid:1)Nt)
`
`SLA’rEm(
`
`I o1. I (cid:1)2
`
`200
`
`tOO
`
`MM Ha
`
`200
`
`A
`2.5
`
`A
`
`5
`
`N
`
`I
`
`N
`
`2
`
`I
`
`2
`
`(cid:1)20522
`5MG/KG
`
`A
`
`2.5
`
`N
`
`I
`
`I
`
`2
`
`420622A
`Ioua,ia
`
`2.5
`
`N
`
`I
`
`2
`
`CAT
`
`- CHLORALOSE
`
`50MG/KG
`
`IV
`
`the
`of
`blockade
`pressure
`the
`blood
`(A), levarterenol
`
`1. The
`FIG.
`pound
`20522
`Epinephrine
`microgm./kgm.
`
`on
`
`UTERUS
`
`effect.
`
`of
`
`inhibitory
`a cat.
`of
`(norepinephrine)
`
`isoproterenol
`
`and
`
`epinephrine
`
`by
`
`com-
`
`(N)
`
`and
`
`isoproterenol
`
`(I);
`
`dose
`
`in
`
`BP
`(cid:1)Ho
`
`20522
`5.OMG/KGL%L
`
`EPI
`
`2.5
`
`SOP 2.5
`
`IV.
`
`FIG.
`(ISOP)
`
`2. The
`blockade
`by compound
`
`SOP 2.5
`EPI 2.5
`CAl- CHLORALOSE
`
`- - SOP 2.5
`50MG.4(cid:1)S
`
`of the inhibitory
`
`effect
`
`of
`
`epinephrine
`
`(EPI)
`
`and
`
`isoproterenol
`
`20522
`
`on
`
`the
`
`uterus
`
`in
`
`situ
`
`and
`
`blood
`
`pressure
`
`of
`
`a cat.
`
`or
`more
`
`substantially
`than
`
`Three
`
`hypertemisive
`
`three
`additional
`effect
`
`reduced.
`hours
`
`in
`
`cat
`
`of
`
`The
`a
`blood
`epinephrine
`
`of Dihenamimie
`nnimiute
`and
`t.his
`series,
`istic
`fall
`
`w’ere
`followed
`the
`imijection
`imi blood
`pressure
`
`given
`by
`
`a
`
`of
`
`5 microgm./kgm.
`with
`little
`
`or
`
`no
`
`epinephrine
`of
`preliminary
`
`caused
`
`a
`
`rise. Compound
`
`character-
`20522,
`
`blocking
`preparations
`
`few
`
`action
`
`compound
`of
`the
`in which
`were
`experiments
`blocked
`by Dibenamine.
`doses,
`each
`injected
`pause.
`One-half
`hour
`
`for
`
`the
`
`20522
`test
`done
`
`was
`
`in
`
`over
`after
`
`persisted
`prolonged.
`which
`Ten
`mgm./kgin.
`a period
`of one
`completion
`of
`
`pressure
`
`was
`5 divided
`in
`two-minute
`
`Page 3 of 9
`
`

`
`INHIBITORY
`
`At)IIENEII(.I(’
`
`mmmA)(KAI)m:
`
`483
`
`1958
`
`.3 mgm.
`epimiephrimie
`kgm.
`of
`
`kgmii.,
`
`I hen given
`
`was
`
`reduced
`injectiomi
`
`the
`
`(see
`
`20522,
`
`rats,
`
`imig
`i midicat
`10 mgm.
`kgni.
`
`incomplete
`of
`I)ibenamine,
`
`an md 1cmi mlii mintes
`Temi
`3).
`fig.
`epimmephrimie
`of
`Dibemmanmide
`
`blockade.
`
`epimiephmitie
`
`caused
`
`lat em the
`depm’ess
`ani :i(hhtionial
`niimiutes after
`caused
`a pmess(
`ir m’espommse
`after
`blood
`
`tise
`)m m’esp
`to
`10 miigmii.,
`all
`three
`ad(Iit
`
`iii
`
`iomial
`
`au
`
`itt
`
`l)messtlme
`
`less
`
`a
`
`hour
`( )mie
`fall
`of
`kgmn.
`alnnost
`
`than
`
`teen
`
`that
`
`first.seen.
`mnimiutes
`later,
`
`After
`the
`
`inject
`
`this,
`
`10 mgm.
`another
`of
`epimiephrimie
`
`ion
`
`was
`
`20522
`devoid
`
`gi’%(cid:1)((cid:1)1i.
`was
`of’ effect.
`
`lou,’-
`These
`
`expemimiiemits
`I)ibemiamine
`indicate
`that
`
`comifimm
`
`the
`
`suggestion
`
`is
`
`20
`
`sufficient
`
`to
`
`to
`
`25 mgm.
`
`block
`
`kgm.
`
`of Nickersomi
`the
`
`excitatory
`
`(1949)
`
`that
`
`effects
`
`of
`
`20522
`
`will probably
`
`nigmn.
`20
`of epinephrine
`blo(’k
`the
`
`kgmu.
`
`of
`and
`inhibitory
`
`effects.
`mi
`
`two
`
`dogs,
`
`imijection
`
`of
`
`isopmoteremiol
`
`into
`
`the
`
`femoral
`
`artery
`
`distal
`
`to
`
`a
`
`of
`
`the
`
`excitatory
`
`and
`
`inhibitory
`
`eflects
`
`of
`
`eJ)inel)lirini(’
`
`by
`
`FIG. (cid:1)3.
`blockade
`Selective
`amid 20522.
`1)ibenamine
`In each block, epinephn’i nie5 niicn’ogni./ kgni . was giveni. .(cid:1)-
`Iit’fore
`lien’
`eu
`./ kgnt.
`l3-3()
`I )iheniantinie,10 nngni
`(‘-2t)
`es aft en’ 20522,
`niinitmtes
`after
`niiilitnt
`I )-18
`10 nigni
`of 20522.
`E--- 52 nainnmnt
`milliltes
`after
`an
`addit
`ionial
`es
`after
`./kgnt.
`10 mgm./kgm.
`of Dibenaminie.
`F-14
`minutes
`after
`an
`additiomial
`10 mgm./kgnn.
`
`I tlorki
`.5 nignn./kgnii.
`ant
`a(l(lit
`
`nig ageni
`
`innal
`
`of
`
`20522.
`
`Page 4 of 9
`
`(cid:1)
`

`
`484
`
`POW’ELL
`
`ANt)
`
`SLATELt
`
`Vol.
`
`122
`
`Sliipley-\\ilsoti
`kgni.
`(lose
`
`rotamneter
`
`cttuse(l
`
`a
`
`tramisient
`
`imicrease
`
`of
`
`compoumid
`
`20522
`
`givemi
`
`l)y
`
`the
`
`same
`
`it!
`
`route
`
`blood
`did
`
`flow.
`not
`
`A 1 nigni./
`alter
`blood
`
`l)tllse
`\Vhemi
`an
`(aused
`to
`prior
`experimemits
`of
`comupound
`
`but
`rate
`blood
`the
`imicrease
`
`treatment
`
`there
`flow
`
`flow
`
`in
`w-ith
`the
`
`with
`20522
`
`flow
`
`blood
`of
`admuinistration
`of
`that
`
`which
`
`through
`isopro-
`been
`
`of
`had
`
`a
`was
`returmied
`
`of
`
`only
`
`imicrease
`transiemit
`normnal,
`to
`per
`cent
`40
`20522.
`compound
`isolated
`St.rauh
`imi a
`comicemitratiomi
`
`frog
`of
`
`heart
`1-100,000
`
`preparation,
`not
`only
`also
`decreased
`
`but
`
`failed
`
`ad-
`failed
`
`to
`
`both
`
`amid
`
`Pmessum(cid:1)e
`the
`artery.
`teremiol
`observed
`three
`lii
`miiimiistratiomi
`I 0
`
`alter
`
`the
`either
`the
`respomise
`
`rate
`to
`
`force
`or
`epinephrimie.
`
`of
`
`of
`comitract.ions
`More
`comieentrat.ed
`
`the
`
`heart
`solut.iomis
`
`rate
`
`of
`
`the
`
`heart
`
`beat
`
`and
`
`at
`
`the
`
`same
`
`Because
`compoumid
`
`of
`
`after
`
`chamige
`force
`amid
`chromiotropic
`heart
`rate
`
`response
`Normal
`
`epinephrimie.
`seen
`
`of
`effects
`ilmi(l
`comitractility
`remnains
`doubt.
`rhythmic
`movements
`
`in
`
`time
`the
`20522,
`
`the
`blocked
`comisiderable
`the
`specificity
`
`inot.ropic
`decrease
`of
`
`and
`in
`this
`
`of
`
`the
`
`isolated
`
`rat
`
`uterus
`
`in
`
`all
`
`four
`
`preparations
`
`consistently
`were
`l-2,000,000.
`
`Doses
`
`inhibited
`of
`the
`
`by
`amialog
`
`isoproterenol
`which
`
`not
`did
`the
`to alter
`20522
`completely
`isolated
`rabbit
`not
`change
`activity
`
`as
`concentrations
`with
`motilit.y-10
`uterine
`inhibit
`of isoproterenol.
`effect
`inhibited
`motility
`intestinal
`strips,
`a
`of
`strips
`but
`
`dilute
`
`as
`and
`
`a
`
`rat
`
`With
`the
`of
`1-10,000,000
`did
`diminish
`
`the
`
`ml.---failed
`compound
`the
`five
`did
`analog
`isoproterenol.
`resistance
`the
`method
`cause(l
`
`100
`
`on
`
`microgm.
`20
`per
`dilutiomi
`1-100,000
`of
`uterus.
`However,
`comicentration
`the
`of
`imihibitory
`of
`effects
`Whemi
`intrapulmonary
`pithed
`(logs
`according
`of
`ergotoximie
`nigmJkgm.
`this slight degree
`10 mgm.
`kgnn.
`
`to
`
`to
`
`air
`of
`slight
`
`a
`
`ivas
`
`flow
`(1939),
`Jackson
`bronchoconstriction.
`
`determined
`
`in
`
`decerebrate-
`
`administration
`In
`
`some
`
`0.5
`of
`experi-
`
`nients
`S and
`
`of
`(loses
`
`bronchoconstriction
`of
`comiipoumid
`
`could
`In
`
`be
`our
`
`partially
`usual
`
`overcome
`test.s
`for
`
`by
`
`bron-
`
`20522.
`
`Ftc,.
`4. Antagonism
`induced
`bronchospasm
`The
`upper
`ung, 1)100(1
`pressure.
`and
`mgnn./kgni.,
`20522,
`3 mgm./kgni.,
`
`tracing
`
`(‘l)inieplirimie
`niephrinme-induced
`
`caused
`
`bronchodilator
`the
`of
`20522
`by
`hed
`dog.
`in decerebrate-pit
`the airflow through
`records
`6 microgm./kgm.
`Epineplirinie,
`at P, pilocarpimie, 0.1 mgm./kgm.,
`at point indicated
`was
`given
`bronchodilatation.
`was
`reduced.
`
`transient
`bronchodilatation
`
`action of epinephrine
`
`on l)ilocarpine-
`
`the tracheal
`and
`caninula
`lower
`the
`givemi at each
`A. At E, ergotoxine,
`were
`given
`intravenously.
`Compound
`after
`it had
`been
`demonstrated
`that
`Aft.er
`administration
`of
`20522,
`
`trac-
`0.5
`
`epi-
`
`the
`
`Page 5 of 9
`
`

`
`1958
`
`INmItBITotlY
`
`%(cid:1)I)tiENt(cid:1)ttG1(
`
`flLoCK(cid:1)DE
`
`poteml((cid:1)’,
`chodilator
`kgmn.
`0. 1 mngnii./
`(cid:1)vith
`a miiarked
`
`amiimiials
`the
`pilocarpine
`of
`inicrease
`of
`
`(cid:1)s’ere
`which
`ititl’al)ultiiOtiarS’
`
`givemi,
`resulted
`
`to
`imi a(l(litiomi
`imi an
`imitemise
`resistance
`to
`air
`
`(lose
`
`a
`ergotoximie,
`1)ron(hoconstrictiolm
`flow’.
`i’he
`a(lniinistra-
`
`48.(cid:1)i
`
`of
`
`(‘it her
`t iou
`of
`bromichodilatatiomi
`bronchioles
`
`isoproterem
`that
`thus
`ami(l
`it had
`l)eeml
`
`iol
`allo(cid:1)ved
`saved
`
`om(cid:1) (cid:1)1(cid:1)j miephri
`passage
`ammimal
`
`the
`
`mie
`of
`
`fromn
`
`usually
`a mnoderate
`death
`preparation
`
`demomistrated
`
`that
`
`the
`
`After
`
`m(cid:1)imie Ot
`As
`
`imifigure
`
`isoproteretiol,
`showmi
`of epimiephrimie
`respomidimig
`isoproteremiol
`
`or
`
`comiipoumid
`
`20522
`
`was
`
`given
`
`4, followimig
`was
`
`comisiderably
`
`admimustratiomi
`
`reduced.
`
`adequately
`
`to
`
`the
`
`stamidard
`
`a
`
`l)roliiPt
`air
`of
`
`I i(cid:1)ati
`through
`
`sieli
`
`the
`
`by
`
`induced
`amnount
`asphyxia.
`was
`
`to epineph-
`respomisive
`10 nigm./
`to
`0.5
`of the amialog, bromichodilator
`which
`cases,
`of
`epi-
`
`imi
`
`(loses
`
`of
`
`Imi several
`
`bromichodilator
`
`amiimnals
`
`(lose
`
`lost
`
`their
`
`respomisivemiess
`
`and
`
`died
`
`of
`
`asphyxia
`
`after
`
`by
`
`kgm.
`efficacy
`had
`been
`nephrimie
`20522.
`A
`simnilar blockade
`
`of
`
`the
`
`relaxatiomi
`
`and
`
`isoproterenol
`
`was
`
`our
`
`experience,
`
`respomises
`
`epimiephrine
`chain.
`In
`epimiephrimie
`pretreated
`strated
`
`with
`
`of’
`tracheal
`demonstrated
`of
`the
`isolated
`
`smooth
`
`mnuscle
`
`ili(luCed
`
`on
`
`the
`
`guitiea
`
`pig
`
`tracheal
`
`guinea
`
`pig
`
`tracheal
`
`chain
`
`to
`
`vary
`treatmnemit
`with
`pilocarpitme,
`epimiephrimie.
`
`As
`
`wit
`
`repeated
`Ii
`inhibitory
`an
`is showmi iii figure
`
`is
`preparatiomi
`the
`if
`How’ever,
`(loses.
`be consistently
`demoti-
`can
`respotise
`5, epimiephrimie
`imi amnoumits
`of
`10
`to
`
`200
`Two
`
`microgmil.
`
`hundred
`
`100
`Per
`micrognn.
`
`ml.
`of
`
`pilocarpuie-imiduced
`the
`relaximig
`effect
`of
`
`epimiephrimie
`
`overcomne
`
`by
`
`larger
`
`(loses
`
`reduced
`fluid
`bath
`of
`20S22
`pe1(cid:1)
`comupound
`but
`after
`comistrictiomi,
`cotisiderably
`was
`of epimiephrimie. Another
`
`the
`100 ml.
`
`pilocarpimie-imiduced
`of bath
`fluid
`
`spasm.
`miot
`alter
`
`di(l
`
`minutes
`This
`
`five
`reduced.
`addition
`
`of
`blockade
`
`of
`
`200
`
`exposure
`could
`microgm.
`
`the
`be
`of
`
`Epinephrine
`
`1t(. a.
`of
`k(cid:1),le(’t
`(‘I)iti(’l)lln’inieani(l
`doses mi microgm./100
`
`20522
`bath.
`
`ml.
`
`O(cid:1)
`
`g(cid:1)niniea
`
`pig
`
`I na(’lIeuI
`
`(‘l(cid:1):iiIi
`
`.
`
`Page 6 of 9
`
`

`
`486
`
`comnpoumid
`
`larger
`
`dose
`
`partially
`(lifhculty
`respomisi
`frequently
`
`imigs
`
`at
`
`POWELL
`
`AX(cid:1)
`
`SLATEII
`
`Vol.
`
`122
`
`20522
`
`per
`
`100
`
`ml.
`
`of
`
`epinephrimie.
`
`this
`
`bath
`of
`However,
`these
`Imi
`action.
`analog,
`away
`following
`epinephrine
`sensitivity
`recover
`their
`of
`15
`20 minutes.
`sinnilar
`and
`
`the
`
`to
`
`experimemits,
`
`2’ ,5’-dichloropheiiyl
`
`the
`
`of
`
`pilocarpine
`compound.
`
`spasm
`
`the
`
`of
`
`blocked
`fluid
`50 mnicrogm.
`experimnents
`anAl
`preparatiomis
`rat
`must
`admi
`to
`epimiephrimie
`
`3’-chlorophemiyl,
`derivatives
`to
`a
`
`but
`
`somewhat
`
`imihibitory
`
`epinephrimie
`
`action
`
`per
`
`we
`
`have
`that
`
`consistently
`have
`
`the
`of
`100 ml.
`had
`their
`
`lost
`
`ioti
`
`of
`evemi
`
`compound
`after
`5 or
`
`20522
`6 (cid:1)(cid:1)‘ash-
`
`also
`
`4’-chlom’ophenyl,
`i)locked
`lesser
`
`epinephrine-
`degree
`than
`
`2’
`
`,4’-
`
`the
`
`of
`
`20522
`
`(cid:1)vith
`
`somne
`
`increase
`
`in
`
`overcamne
`imi washing
`veniess
`to
`fail
`to
`intervals
`few
`a
`Imi
`(lichilorophemiyl
`imiduced
`relaxation
`:1’ , 4’-dichlorophenyl
`Mi(e
`respomided
`spotitaneous
`muediami
`20522
`
`activity
`dose
`given
`
`lethal
`were
`
`to
`
`the
`
`ititraperitoneal
`
`imijectiomi
`
`similar
`
`to,
`
`but
`
`less
`
`thami,
`
`that
`
`seemi with
`
`amphetamine.
`
`The
`
`by
`
`veimi
`
`was
`
`estimated
`
`to
`
`be
`
`48 mgm./kgmn.
`
`Graded
`
`doses
`
`of
`
`intraperitoneally
`
`to mice
`
`one-half
`
`hour
`
`prior
`
`to
`
`the
`
`intravenous
`
`injection
`
`of
`
`isoproterenol.
`
`As
`
`show-n
`
`in
`
`table
`
`1,
`
`umider
`
`these
`
`circumstances,
`
`pre-
`
`with
`
`treatmnemit
`Discussiox.
`actions
`of
`
`reduced
`20522
`I nhihitiomi
`epimmephrimie
`
`inediami
`the
`bromichodilator,
`of
`compound
`20522
`
`by
`
`of
`
`lethal
`
`has
`
`dose
`vasodilator
`special
`
`drug-receptor
`
`theory,
`
`of
`
`of
`terms
`imi
`affimiity amid
`et.hamiola(cid:1)nimies
`idemitified
`
`by
`
`intrinsic
`
`activity
`
`cami
`the
`
`combitie
`
`term
`
`with
`“adremiergic
`
`particularly
`1954;
`(Ariens,
`a physiological
`imihibitory
`
`isoproterenol.
`a mid other
`relevamice
`when
`the
`of
`1936).
`which
`substance.”
`
`examuple
`an
`as
`Stephemisomi,
`substance
`m’eceptor
`
`imihihitory
`considered
`separation
`phen-
`Many
`is
`tentatively
`The
`comise-
`
`such
`of
`drugs,
`
`end
`
`imi
`
`drug-receptor
`such
`epitiephrimie
`as
`the
`
`vary
`imiteractiotis
`isoproteretiol,
`or
`
`with
`
`the
`trigger
`
`amine
`a
`series
`
`being
`of
`
`studied.
`reactions
`
`respomise.
`appropriate
`biotransformation
`rapid
`admimiistratiomi
`of
`
`The
`
`actioti
`amid/or
`isoproteremiol
`
`of
`
`these
`
`two
`
`compounds
`
`is
`
`loose
`followed
`
`(weak)
`by
`
`is
`
`drug-receptor
`tramisient.
`fall
`
`a
`
`(cid:1)uemices
`Active
`which
`brief
`
`bonding.
`
`imi blood
`
`because
`Thus
`pressure.
`
`of
`the
`
`EJJ’eel
`
`of compound
`
`20522
`
`Oil
`
`/OXi(’it!/
`
`of
`
`isoproterenol*
`
`TABLE
`
`1
`
`Intraperitoneat
`
`20.c22
`
`0 mgm./kgm.
`
`10 mgm./kgm.
`
`20 mgm./kgm.
`
`40 mgm.
`
`/kgm.
`
`intravenous
`
`Isoproterenot
`
`origin.
`
`kt(cid:1),;z.
`
`63
`MO
`1(X)
`125
`160
`
`0/10
`4/10
`9/10
`
`-
`
`2/10
`10/10
`
`-
`
`4/10
`8/10
`
`1/10
`7/10
`
`-
`
`-
`
`-
`
`LD(cid:1)
`
`±
`
`SE.
`
`132.1
`
`±
`
`5.7
`
`110.0 ±
`
`7.2
`
`85.43
`
`±
`
`4.04
`
`74.73
`
`±
`
`3.48
`
`* Compoumnid
`
`20522
`
`given
`
`i nitraperit
`
`oneally
`
`30 mi ntmtes
`
`before
`
`i nt ravenous
`
`administ
`
`ra -
`
`tion
`
`of
`
`isoproterenol.
`
`All
`
`differences
`
`level
`was
`
`of
`
`probability
`
`justified
`
`by
`
`a
`
`the
`by
`‘‘t’’ test.
`low x2 value
`2. 1.
`
`of
`
`between
`this
`
`In
`
`values
`LD50
`compumtation.
`
`are
`the
`
`significant
`use
`of
`
`5 per
`
`at
`
`the
`combined
`
`cent
`slope
`
`the
`
`Page 7 of 9
`
`(cid:1)
`(cid:1)
`

`
`1 958
`
`INHIBITORY
`
`A I)REXEIIGIC
`
`B L()C KA t) 1’
`
`487
`
`as
`
`Substances
`have
`a more
`receptor
`site
`reduced
`rifle
`is
`inhibited
`
`an
`
`state.
`
`such
`prolonged
`for
`a
`longer
`or
`blocked
`An
`example
`
`are
`
`is
`
`use
`
`rapid
`prone
`less
`which
`ephedrine,
`remain
`presumably
`of
`action,
`duration
`inhibitory
`time
`the
`During
`this
`time.
`(Finklemnan,
`1930).
`Similarly,
`the
`of
`this
`the
`of
`ephedrine
`
`to
`
`and
`the
`
`in
`
`is
`an
`
`a
`
`by
`
`degradation
`to
`attached
`epineph-
`effect
`of
`effector
`organ
`is
`as
`a bronchodilator
`of
`ephedrine
`activity
`for
`evidence
`presumably
`The
`potentiation
`sites.
`receptor
`interpreted
`as
`being
`has
`been
`but may
`be
`related,
`in
`some
`
`studied
`(1-o-chloro-
`broncho-
`active
`showing
`doses
`of pilocarpine-
`than
`is
`less
`isoprophenamine
`epinephrine,
`sites”
`
`amines
`
`an
`
`at
`tone
`
`seen
`it
`
`which
`a pharma-
`
`with
`
`is
`is
`
`or
`
`pharmacological
`activity,
`excitatory
`ephedrine
`oxidase,
`
`some
`
`(Powell
`adrenergic
`of
`doses
`In moderate
`effect
`chains.
`However,
`epinephrine.
`relaxation
`complete
`for
`“adrenergic
`
`This
`
`The
`patients.
`asthmatic
`in
`agent
`pressor
`its
`by
`however,
`complicated,
`adrenergic
`on
`indirect,
`effect,
`direct
`by
`epinephrine
`of
`effect
`of
`the
`pressor
`inhibition
`of monoamine
`the
`of
`consequence
`of
`inhibitory
`sites.3
`blockade
`measure,
`to
`sympathomimetic
`to
`ephedrine
`and
`other
`contrast
`In
`(1949)
`Astrom
`for
`antisympathetic
`activity,
`isoprophenamine
`phenyl-2-isopropylaminoethanol)
`1956)
`is
`al.,
`et
`dilator
`apparently
`excitatory
`effects
`devoid
`potent
`inhibitory
`it decreases
`the
`activity.
`pig
`treated
`guinea
`is
`considerably
`tracheal
`with
`much
`smaller
`after
`of
`doses
`sometimes
`difficult
`with
`obtain
`to
`again
`suggestive
`inhibitory
`conipetition
`of
`cologically
`active
`amine.
`The
`blockade
`seen
`with
`amine
`is relatively devoid
`used.
`Thus
`it
`can
`be
`combination
`that
`postulated
`reactions
`series
`of
`the
`to
`trigger
`inhibitory
`sites”
`fails
`strongly
`suggests
`that
`evidence
`hibitory
`effects.
`Yet
`drug-receptor
`complex
`that
`the
`and
`the
`receptor
`20522
`by
`the
`hydroxyl
`groups
`are
`susceptible
`monamine
`personal
`biological
`stable
`problems
`
`20522
`represents
`a
`of either inhibitory
`
`special
`case
`or excitatory
`
`only
`in
`so
`far
`as
`this
`action in the doses
`
`the
`
`site
`phenohic
`
`deamination
`
`oxidative
`to
`communication),
`life.
`For
`these
`blockade
`and
`should
`related
`to
`adrenergic
`
`20522
`reasons
`prove
`
`it
`
`would
`can
`useful
`mechanisms.
`
`of
`
`20522
`that
`20522
`is
`fairly
`chlorine
`oxidase
`
`to
`
`have
`20522
`study
`
`that
`in the
`
`in-
`with
`
`“adrenergic
`with
`typical
`to
`lead
`combine
`does
`Since
`stable.
`in
`it
`is not
`since
`(Korzenovsky,
`
`and
`
`reasonably
`a
`a
`will
`cause
`of pharmacological
`
`long
`fairly
`
`replaced
`by
`expected
`he
`expected
`a tool
`
`be
`as
`
`,4’ Dichlorophenyl)-2-isopropylaminoethanol
`
`analog
`and
`
`depressor
`
`isoproterenol,
`of
`isoproterenol.
`action
`
`of
`
`1-(3’
`dichloro
`epinephrine
`The
`
`SUMMARY
`
`selectively
`
`blocked
`
`hydrochloride
`some
`inhibitory
`
`(20522),
`effects
`
`the
`of
`
`isoprot.erenol
`
`and
`
`the
`
`secondary
`
`depressor
`
`action
`
`of
`
`some
`In
`20522
`tyramine.
`the
`
`Korzenovsky
`experiments,
`preliminary
`inhibits
`of 0.5 mM/I.
`in a concentration
`may
`be
`of
`special
`interest
`This
`finding
`to
`ephedrine
`can
`be
`attributed
`pressor
`response
`fit with
`such
`a hypothesis
`of monoamine
`oxidase.
`To
`
`(personal
`competitively
`in
`regard
`largely
`20522
`
`that
`of
`that
`hibitor
`agent.
`
`communication)
`the
`oxidative
`to
`theories
`to
`its
`should
`
`found
`ha.s
`deamination
`which
`propose
`activity
`an
`be
`a potent
`pressor
`
`as
`
`in-
`
`Page 8 of 9
`
`

`
`488
`
`POWELL
`
`AND
`
`SLATER
`
`ioi.
`
`1(cid:1)2
`
`inhibited
`fall
`in
`effect
`uterus,
`in which
`analog
`caused
`
`of
`
`dichloro
`the
`by
`pressure.
`blood
`epinephrine
`however,
`the
`analog
`only
`
`on
`
`isolated
`rabbit
`failed
`block
`20522
`caused
`itself
`considerable
`decrease
`slight
`intrapulmonary
`decerebrate-pithed
`dog,
`but
`The
`admninistration
`of
`20522
`of
`release
`this
`bronchoconstriction.
`chain,
`tracheal
`20522
`inhibited
`pilocarpine-induced
`spasm.
`This
`doses
`of
`epinephrine
`was
`Further,
`20522
`drug-receptor
`complex.
`“adrenergic
`inhibitory
`effect.,
`yet
`was
`
`analog
`
`which
`
`of
`
`itself
`
`had
`
`at most
`
`to
`
`of
`
`blocked
`intestine
`relaxation
`epinephrine
`in
`tone.
`decrease
`resistance
`no
`action
`the
`
`was
`
`had
`blocked
`
`to
`on
`
`usual
`
`and
`
`to
`
`iso-
`be
`the
`
`epinephrine
`action
`appeared
`partially
`overcome
`could
`off
`only
`with
`difficulty,
`washed
`It
`seemed
`probable
`that
`20522
`receptor
`sites”
`without
`itself
`competing
`for
`these
`sites
`with
`
`were
`transient
`a
`inhibitory
`On
`rat
`doses
`
`with
`dichloro
`
`epimiephrine
`caused
`The
`20522.
`by
`except
`The
`flow
`air
`pilocarpine
`epinephrine
`On
`isolated
`proterenol
`competitive
`blocking
`suggesting
`combining
`causing
`much
`physiologically
`
`in
`
`was
`
`ergotoxine-treated
`the
`bronchoconstriction.
`or
`isoproterenol
`guinea
`pig
`relaxation
`of
`since
`large
`20522.
`action
`tight
`a rather
`certain
`with
`physiological
`a(tive
`amines.
`
`of
`
`and
`
`REFERENCES
`
`pharniacodyn.,
`internat.
`J.: Arch.
`E.
`scandinav.,
`18:
`A.: Acta
`physiol.
`J.:
`J. C.,
`E.
`DEBEER,
`THIS
`AND
`F. R.:
`35: 333,
`1929.
`JOURNAL,
`THIS
`J. Physiol.,
`B.:
`145,
`1930.
`D. E.:
`Experimental
`Pharmacology
`JACKSON,
`Co., St. Louis, 1939.
`Mosby
`C. M.,
`E. A., GRUBER,
`NEIDLE,
`1951.
`64,
`NICKERSON,
`
`99: 32,
`1949.
`295,
`JOURNAL,
`
`1954.
`
`90:
`
`104,
`
`1947.
`
`70:
`
`AND
`
`COPELAND,
`
`Pharmacol.
`M.:
`C. E., GIBSON,
`1956.
`
`Rev.,
`%V. R.,
`AND
`
`1: 27,
`1949.
`SWANSON,
`
`and Materia
`
`Medica,
`
`2nd
`
`Ed.,
`
`p.
`
`302. C. V.
`
`J. E.: Arch
`
`internat. pharmacodyn.,
`
`87:
`
`E. E.:
`
`J. Am.
`
`Pharm.
`
`A.
`
`(Scient.
`
`Ed.),
`
`45:
`-
`
`R.
`
`P.:
`
`Brit.
`
`J. Pharmacol.,
`
`11:
`
`379,
`
`1956.
`
`ARIENS,
`ASTROM,
`CASTILLO,
`
`CURTIS,
`
`FINKLEMAN,
`
`POWELL,
`785,
`STEPHENSON,
`
`Page 9 of 9