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THE
EFFECT
OXIDATION
l-DWIN
OF
A NUMBER
OF TYHAMINE
FELLOWS2
of
.)fe(licine,
of
.)Iedicine
ANI)
OF
AHALKYLAMINES
BY AMINE
BERN
Pen
fls(/ll’(lll
OX
OXIDASE’
HElM
ia
and
J)uke
THE
J.
FREDERICK
ia,
Temple
( niversit!J
School
School
Philadeiph
f ii ircrsitj
,
I) u rhaisi
,
.\orth
l)uI)lication
and
Quastel,
May
Carolina
Received
It
has
been
suggested
(Mann
for
27, 1950
that-
the
central
stimulant
1940)
action
tion
between
of dl-phenylisopropylamine
by amine
the
is related
desirable
amine
and
to its
oxidase
inhibition
inhibitory
of tyramine
if a correlation
activity
oxida-
exists
aryl-2-
(Nos.
and
it
oxidase.
central
It appeared
excitatory
to determine
l)eta-phenethylamine
of a number
of structurally
aminopropane
i-elated
modifications.
salts
of benzylamine,
and
in the
their
cerebellum
influence
was
nervous
and
compounds
A series
144,
logical
seeme(l
METH0I5.
action
of
of
phenylaminobutane
145)
in
phenylaminopentane
study
because
and
brain
on
used
of
68
an(l
changes
pertinent
are
the
to
included
cerebrum,
investigate
they
amine
to
secure
of
given
produced
stem
oxidase
inferential
rats.
compound.
histopatho-
activity.
data
Effects
in
many
on
of animals,
the
motor
The method
of Szvmanski
present
compounds
01)
the
activity
increase(1
after
(1918)
central
administration
the
in-
in-
system
a
Stimulation
was
noted
ferred
after
if
doses
in
excess
of
25 mgm./kgm.
animals
after
were
higher
not
considered
(loses
suggested
significant
toxic
I)ecause
effects.
stances
were
the
injected
behavior
mt
of the
raperitoneally.
All compounds
The following
method
was
used
to determine
the
effect
of the
present
compounds
on
amine
oxidase:
The brains
of three adult
rats were washed
free
of
blood,
ground
in a mortar
with
.11/20
Na-K
phosphate
buffer
at either
pH 6.7 or 7.8 and squeezed
through
muslin.
The
fitial
volume
was
17.0 ml. One ml.
of
this suspensioli
was placed
in each
50 ml. Erlenmeyer
flask
and
the volume made
up
to
2.0
ml. with
buffer
containing
3.7 X 10
.11
tvraniine
with
or without 3.7 X 10
11
concentration of the (Irug. The vessels were incuhatetl 60 minutes
at
37#{176}C.
air. Each experiment
in
was
run
in triplicate
and
each
(lrug
was
tested
at
least
four
different
times.
At the end of the experiment
2.0
ml.
of
HzO and 1.0
mgm.
20
per cent
trichlor-
acetic
acid
were
added.
The
precipitated
protein
was cetitrifuged
down
and
an
aliquot
of
the supernatant
was distille(1
from
alkali
into
acid
and the NH3
estimated
colorinietricallv
after
Ness!erization.
deamination
of
The
tyramine.
results
are
expressed
significant
measurement
as
the
average
difference
of
percentage
in
ilihil)itioli
of
the
hydrogen
latter
ion
inhibits
concentrations
There
was
no
use(l. Direct
of tvramine
uptake
was
these
oxidation
the
inhibitory
values
at
the two
effect of these
coni-
product
of the
l)oun(ls on the
oxidation
the
oxygen
not
feasible
since
the
of
brain.
shown
data
on
compounds
excitatory
which
effect.
were
The
entirely
valid-
DIscuSsIoN.
In
table
only
1 are
an
devoid
of or
possessed
degree
igat
insignificant- central
it-y of the
I
of tyramine
ion
was
supported
oxidase
inhibition
part
by
obtained
the Snaith,
and
FI-ench
with
Kline
the
and
compounds
French
Laho-
This
invest
in a large
1)ivision,
Snail
ratories
Fellowship
2
Present
address:
delphia,
Pennsvlvaliia.
Fund.
Hesealch
ha, Kline
Laboratories.
Phila-
94
TABLE
Compounds
STRUCTURE
COM-
POUND
1
excitatory
effects
devoid
of central
32
4”l
555__
INIII-
DOSE
EFFECT
B!-
No.
3
6
TION
SUBSTITUTION
mgm./kgm.
Per
cent
143
141
27
22
14
1-CH2-NH2.
HC1
4 H2S04
4
H2SO4
HC1
H2SO4
25
25
25
10-25
No side effects
No
side effects
10
0
1-CHNH2-CHCH3
1-CH2---CH2-NH2-
1CH2CH2NHCHzC6H
1-CH2-CHNH-CH3.4
4-OH
1-CHOH-CHNH2-CH3
Depression
Depression
8
11
effects-
on
effects
10-25
No
side
(lepressi
30
45
25
No
side
0
4-OH
38
1-CH2-CHNH,-CH3.
3-OCH3
4-OCH3
HC1
15-25
No
side
slight
tioii
side
slight
t
ion
effects-
stimula-
12
20
1-CH2--CHNHCH2CH,OH-CH3-
4H2S04
10-25
No
effects-
stimuha-
effects-
3
88
1-CH2---CHNHC4H9---CH3-
4-OH
1-CH2-CHCH3-NH-CH2-CHCH3-C6H5
HBr
10-25
No
side
0
slight depression
25
Slight
tion
stimula-
138
9
HBr
41
1-CH2-CHCH3-NH-CH2-C6H4-
COOC2H5(p)
.
25
No
side
effects
6
HC1
10-25
90
1-CH2-CHCH3-NCH3CH,CH,---COOC2H5
No
HCI
side
effects-
very slight stim-
ulat ion
side effects
side
effects-
1
86
1-CH2-CHN
(CH3)2-CH3
25
No
No
2
4-OH
48
1-CH2CHNH2C2H5
12.5-25
Depression
-
15-25
10
4-OH
83
1-CHNH2-CH2-C6H4-OCH3-(p)
4-OCH3
Slight depression
20
16
“-CH2-CH2---NH2.HCl
L\H
10-25
Depression
0
/
95
96
EDWIN
J.
FELLOWS
AND
FREDERICK
BERNHEIM
TABLE
COM-
POUND
1-Continuei
INHI-
-
DOSE
EFFECT
SI-
NO.
TION
-
mg,,z.kgn.
---
217
/\
25
No
side
effects
11
CH3_LN
)-CHz-CI1NHz-CI-I3
103
-
211 CI
r’-C=O
25
No
si(Ie
effects
0
li-C
uN H-(
2l-L-H Cl
103 B
-\-C=O
25
No si(le
effects
J
I
\\(lI_CIINli2(2H5
.
II(/l
124
/
-(‘=0
25
No
side
eftects
1
,,,,J-CII-Cl-INHC4hi9-C21L
[ICl
in table
and
1, with
it is within
the
the
exception
limits
of
pai-a-hydroxyphenyl-2-aminopropane
(No
error
of
.
(No.
83)
is
quest
ional)le
Although
method.
14)
1)e-
the
l -amino-
I , 2-di(para-met
hoxyphenyl)-ethane
of experimental
cause
the
enzyme
was
No.
14 ma
explanation
obtained
from
rat brain
tissue,
the
1)e referable
to its marked
pressol.
for
the
high
inhibitory
on
those
of pronounced
-
high inhibitory
activity.
There
83.
derivatives
of the
agents
per
cent
central
inhibition
value
is no
noted
apparent
which
for
activity
of
No.
fable
hibited
in (loses
hibition
Oxi(lase
to
marked
w’ell
2 contains
effects
of 25
of
was
the
suggestive
data
kgm.
aryl-2-aminopropane
stimulation
cx-
in-
nervous
of the
system
amine
mgm.
shown
ot-
less.
of
All
of these
A 32
to
3.0
produced
a significant
deamination
tyramine.
of
1.5
by
dl-phenvlisopropylamine
in (loses
oxidase
that
of its
3).
(No.
mgm.
activity
isomer
to
used,
on
(No.
stimulation
1) which
produced
slight
kgm.
The central
excitatory
of
the
could
however,
dl-phenylisopi.opylamine
(No.
report
be
2)
as
(No.
as
the
less
amine
inhibitory
dextrc-rotatory
This
1) is-as
no
effect
vitro
than
isomer
but
by
greater
l3eyer
for
respiration
corresponding
than
(1946)
the
that
that
optical
The
in
of its levo
consistent
(No.
difference
is in contrast
behavior
He
system
and
same
in
enzymatic
detected
liver
forms
on
of dl-phenylisopropylamine.
the
central
(No.
4-a)
10)
nervous
is
Nos.
and
its
pi-eparations.
depression
4)
and
as
of brain
their
of
dl-N-methylphenylisopropylamine
of
the
1 and
analogues,
(No.
d-N-methylphenyl-
isopropylamine
magnitude
primary
2-aminopropane
amino
2. In
spite
of the
fact
(No.
that
25)
(/l-cyclohexyl-
are only
one-
N-methyl
modification
ARALKYLAMINES-AMINE
OXIDASE
97
tenth
fications
10
and
table
as potent
motor
activity
stimulants
as their
corresponding
phenyl
modi-
(Nos.
1 and
25 is entirely
4), the decreased
amount
comparable
with
Nos.
of tyramine
deamination
of Nos.
1 and 4. Of all the compounds
in
(No.
42)
manifested
the
highest
de-
2, para-met-hylphenyhisopropylamine
TABLE
2
ert’ous
system
stint ulation
at
25nigm
./kqiit.
Compounds
causing
marke(l
uncomplicated
central
STRUCTURE
POUND
DOSE
EFFECT
SUBSTITUTION
-
mgm/
kgm.
Per
cent
1
1
CH2CHNH2CH31
H2SO4
(dl)
1.5_3.0
S-light stimulation-
marked
stimulation
32
2
3
1CH2CHNH2CH34
1CHzCHNH2CII3’4
H2S04(d)
HS04
(1)
2.0
2.5-10
Marked
No
stimulation
effects-
stimulation
49
21
side
marked
4
1CH2CHNHCH3CH3HCI
(dl)
l.5-3.0
Slight
marked
stimulation-
stimulat
ion
25
4a
1-CHz-CHNHCH3-CIIi-HCI
1-CH2-CHNH2-Cl13.1
4-CR3
(d)
1iS0
2.0
10-20
Marked
stimulation
36
65
42
Slight
stimulation-
marked
stifliUlatiOli
Slight
stimulation-
marked
stimulation
Slight
stimulation-
marked
stimulation
Slight
stiniul
5
1-C112-CHNH2-CI13HCI
3,4-CH2O2
1.0-10
14
149a
1-C112-CHNH2-C2H5-1
H2SO4
.5.0-20
20
-CH\H
-CH,
HCI
10-20
marked
ttion-
st imulat
ion
32
25
-
“-CH3-CHNHCH3-CH3.HCl
10-21)
Slight
marked
stimulation-
33
stiniulatioli
gree,
activity
with
65 per cent,
is only
oxidation
of inhibition
that-
of
the
of
No.
by
amine
oxidase,
but
its
central
excitatory
one-fifth
of
tyramine
1. It
is to be noted
(No.
5) was
that
(No.
the
less
interference
and
2-
2-amino-1-phenylbutane
necessary
to
produce
central
149-A)
amino-1-(3
As indicated
,4-methylenedioxyphenyl)-propane
in table
2 the doses
far
than
No.
42.
with
stimulation
98
EDWiN
.r.
FELLOWS
AND
FREDERICK
BERNHEIM
No.
kgm.
All
were
5 or No.
of the
included
149-A
varied
over
a range
of 1 to 10 mgm./kgm.
afl(l
-4-aminopentane
found
3
in mo-Pen
tane
3lodificat
and
5 to 20 mgm./
which
inhibi-
,
respectively
1 -phenyl-3-aminobutane
in the
present
studies
modifications
a significant
were
TABLE
1 -Phen
to
manifest
,/-3-.-l
inmo-B
STRUCTURE
utane
or 4-A
ions
POUND
4l
SUBSTITUTIONS
DOSE
EFFECTS
,ngm./
Per
cent
k(,n.
144
iCH2-CH-CHNHz-Cfl
ILSO4
15-25
No
side
effects-
very
slight
stimulation
67
63
iCIiz-CH-CIlNIIz-CHz
4-01-I
1(’II2CHCl1NIL-CH1
4-Cl-I3
IIBr
25
No
side
effects
27
172
IIzSOa
5-25
No
side
convulsions
effects-
(death)
67
1-ClIz-CHz-CIINIIz-CzFL’
4-OCII3
HC1
1-10
1)epressioli-
47
convulsions
(death)
64
ICII2CIIzCI1NHzCII:rHCl
3,
4-CH2Oz
10-25
Slight
015
stimu-
iS
lation-trem-
68
1CIIzCHzCHNIICIIi’HCl
3OCIT
4-OCI-13
25
No
si(leeffects
17
145
1-C112-CH2-CH2-CI--INH2-CH31
l-ISO
20-25
Slight
stimu-
ion
side
effects
34
lat
71
1CHzCHCH.-CIINIj---CH:;HBr
4-01-1
25
No
21
-
72
iCIlz-CHz-C1ICiINHz-CHi
4-OCH:
HC1
10-25
Depression-
convulsions
38
tory
lant
phenyl-
(No.
action
action
(No.
145)
on
on
amine
the
63)
its
phenyl
an(l
oxidase
central
parent
(table
3).
system
Either
was
(No.
analogue
no
effect
or
after
only
the
a slight
para-hydroxy-
as
well
as
stimu-
their
nervous
Observe(l
144)
or
(No.
3 ,4-dimethoxyphenyl-butane
compounds
derivatives
71).
unsubstituted
and
4-amino-1-phenylpentane
Although
outstand-
para-hydroxyphenyl

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