1955_cerletti_2525_1.pdf

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M 377 psychotic effect of LSD
M 500 properties of
LSD
M 502 properties of B0L
antagonism serotonin
to
(§90a)
Sandoz_ R_iei_,
and its
bI_ B_L No.j (§91c)
LS'D No.120 (§102a)
CW_T'TI,
Ao _ ROTHLIN, E° (Dept.of _armacol°,
)tamine _u msntal diseases
acid deriv_:t
ires.
T_
po_ibility that
5-hydro_ryptamine
p_;_ye
p_t in abnormal mental proeessea has been, di_o
cuaqed by
G_ddum
t
and
by Wooliey
and
Shaw z The
hypoth_
is baaed on the findings that this _ub-
st_c_ is a natural constituent
of
nervous tissue,
particularly
of the brain s, and
that
certain
oi" its
actions
are
antagonized
by lyaergie
acid
dieChyL
amide
_, a drug
which
on oral application
and in
doses of
only
0-5--1.0
tzgm./kgm,
produoes
prono_,meed
psychic
disturbances
in normal
human
being_ 5.
According
to
this hypothesis,
the
effects
of lysergie
acid
diethylamido
result
from its antagonistic
effect
on the
5-hydroxytryptamino
in the brain.
In the course
of screening
derivatives
of lys_rgic
acid
diethylamide
for 5-hydroxytryptamine-blocking
effects,
we have
found
in 2-brom-d-lyaergic
ucid
diothylamide,
coded
BOL
148, a
compound
which,
like ly_ergie
acid diethylamide,
strongly
antagxmizes
certain
effects
of
5-hydroxytryptamino,
but
unlike
ly_ergic acid diethylamide
does not produce
abnormal
psychic
disturbances.
The
introduction
of one
bromine
atom
into the molecule
of lysorgie
acid
diethylamide
thus completely
alters
its activity
: it
lose_ the characteristic
property
of producing
psychic
disturbances
in man
but
retains
the
strong
anti-
5-hydroxytryptamine
action
_'hen
comparing
the central
and peripheral
effecfs
of lysorgic
acid diethylamide
with those of
BOL
148,
pronounced
diff_rences
were founds.
In normal
and
waltzing
miee_
lysorgic
acid
diethylamide
causes
excitation,
whereem
F;OL
148 has a sedative
effect.
_n cats,
small
doses of the former
cause
a
fall in
_rteria_. blood proa_ure
and bradycardia,
whereas
the
_tt_r_
tested
in doses up
to 1
mgq_./kgm.,
was
prae_
tically
inactive.
Again,
th_ former
has a strong
stimtflating
effe_:t on the
rabbit
uterus
in xit_,_
whereas
the latter is practically
inactive.
_Vo have
also tested
BOL
148 on ourselves
and on some of
our laboratory
staff.
It never
produced
signs
of
mental
or psychic
disturbancos
such as we rogalarly
observed
after lysergie
acid
diethy_.ami(lo,
even whe_
used in doses twenty
times as great.
There was orri
S
a certain
sedative
action,
co,misting
in a feeling of
general
fatigue
and
son_e_imr_
slight
n_i_,_ea.
In spite of the fact th_,t _.he t)harmacologic_l
eiTevts
of
BO.L
148 differ so cornplet_,ly
from those
of
lysergi_
acid diethylamide
in animals
as well as in humans,
it was found to share with, the latter
the strong
ax_ti-5-hydrox_tm_nin_
action.
Ersoamer _ had
shown
that
lyeergio
acid die_hylamide
is
a
strong
antagonist
to
5-hydroxytrypt_nine
on
the
isolated
rat uterus.
On
this preparation
and on the
isolat_i
perhmed
kidney
of the rat,
BOL
148 was found to
be am even stronger
antagonist,
being about
a half
times
as
active.
In other tests
BOL
one and
148 was
found
to
have
approximately
the
same
anti-5-
hydroxytryptamine
action
as lyesrgic
acid diethyl-
amide,
for example,
in antagonizing
the effects
of
intra-aortic
injections
of 5-hydroxytryptamine
on
the arterial
blood
pressure
and the renal and
rues-
enteric blood flow of the cat,
in
blocking the broncho-
constrictor
effect
of
5-hydroxytryptamine
and in
antagonizing
its
potentiating
effect
on
barbiturates.
The
anti-5-hydroxytryptamine
effect
of
BOL
148 is
highly specific
; in
doses which fully
antagonized
the
action of 5-hydroxytryptamine,
BOL
148 showed
no
signs of an
antihistamine,
antiadrenalino
or anti-
acetylehoKue
effect.
As
the
hypothesis
of the cerebral
functions
of
5-hydroxytryptamine
is
based
to a great extent
on
the fact
that
lyserglc
acid
diethylamide
is
a strong
antagonist
of 5-hydroxytryptamine,
the present
find-
ing that
BOL
148
is
as active
as
lysergic acid diethyl.
amide
in antagonizing
5.hydroxytryptamine
but
produces
none of
the
mental
disturbances
makes
it
neceesa_j
to
reconsider
this hypothesis.
It
cannot
be argued that
BOL
148
lacks cerebral
actions
because
it does not penetrate
into
the brain
tissue;
the
sedative
action
it
produces
is a
central
effect.
In
addition,
after
an
injection,
BOL
148 could
be
detected
in
the same
indirect
way
as lysergic
acid
dlethylamide
in
extracts
of the brain,
when tested
for
anti-5-hydrox]rbryptamine
activity.
Brain
ex-
tracts of
mice
previously
injected with either
BOL
148
or
lysergic
acid diethylamide
exerted
anti.5-hydroxy-
tryptamine
activity
s.
Our results
with
BOL
148
thus
make
it difficult
to correlate
the
psychic
effects
of lysergic
acid
diethylamide
with
its
anti-5-hydroxytryptamine
property.
At present, we
are
not justified
in
assuming
a causal
relationship
between
these two properties
of lyesrgie
acid
diethylamide,
although
it
may
eventually
be
found that the 5-hydroxytryptamine
in
the brain
is involved
in the central
actions
of
lysergic
acid
diethylamide.
The mere
fact of
a
pharmacological
antagonism
between
lysergic
acid
diothylmnide
and
5-hydroxytryptamlno,
however,
no longer
provides
evidence
for the hypothesis
that
inhibition
of the latter in
the
brain is the
cause
of
the mental
disturbances.
J
Gaddum,
J. H., Ciba Foundatton Symposium on Hypertension,
London (J. and A. Churchill, Ltd., 1953).
* Woolley, D. W., and Shaw, E.,
8c/enee,
119, 587 (1954) ;
Brfl. Med.
J.,
ll, 122 (1954).
' Amln, A.
H.
T.. Crawford, B. B., and
Gsddum.
J. H., International
Physiological Congreu, Montreal, 1958, p. 165. Twarog. B. M.,
and Page, J. H.,
Amer. J. Phys/o/.,
175, 157 (1953).
' Gaddum, J. H.,
J. PAye/o/.,
121, 15P'(1953).
s
See Sloane, B., and Lovett Doust. J. W.,
J. Ment. 8el.,
100, 129
(1954), for a recent Itummaryo_ work in this field.
• Rothlln. le and Cerletti, A.,
Helv. Phl/*iol. Aeta.
10, 319 (1952).
' F_pamer, V.,
Are& I,V.ernat. P/,z_Vn.,
98, 293 (1953).
' Lanz, U., Cerletti, A., and Rothlin, E.0
Hdv. Phlndol. Pharmacel.
A_a
(in the press).
we
(E 7967) mCr/bh1155
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