This is a recipe from PiHKAL
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of 33 g 3,4-dimethoxybenzaldehyde
in 140 mL
acetic acid was treated with 23 mL nitromethane
and 12.5 g anhydrous
, and heated on the steam bath for 45 min. To this
there was slowly added, with good stirring, 300 mL H2O, and the
resulting solids were removed by filtration. The product was finely
ground under a small amount of MeOH, filtered again, and air dried to
give 13.5 g 3,4-dimethoxy-beta-nitrostyrene
with a mp of 142-143 °C.
To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O
was at a gentle reflux and under an inert atmosphere
, there was added
11.45 g 3,4-dimethoxy-beta-nitrostyrene
by leaching it from a thimble in
a modified Soxhlet condenser
. The addition took 2 h and the refluxing
was maintained for another 16 h. After cool-ing to room temperature
the excess hydride
was destroyed by the cautious addition of 500 mL
1.5 N H2SO4. The phases
were separated, and to the aqueous phase
there was added 250 g potassium sodium tartrate
. The pH
to >9, and the clear solution
was extracted with 3x100 mL CH2
Remo-val of the solvent
from the combined extracts under vacuum gave
5.2 g of a pale yellow oil. This was dissolve
d in 300 mL anhydrous
and saturated with anhydrous
HCl gas, giving 5.0 g of a slightly
sticky off-white solid. This was recrystallize
d from 75 mL of boiling
to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride
as beautiful white crystal
greater than 1000 mg.
(with 500 mg) Nothing.
(with 1000 mg) Nothing.
(with 10 mg i.v.) RNothing.
(with 1000 mg of 3,4-dimethoxyphenylacetic
acid, a major human
of DMPEA) RNothing.
(with 500 mg of N-acetyl
, a major human
of DMPEA) RNothing.
EXTENSIONS AND COMMENTARY:
Why all the interest? Why keep pursuing a
compound that is so obviously without activity? Or a metabolite
is also without activity? The answer is that these are totally
fascinating compounds just because they have no activity! By the way,
in this instance, I actually made up most of the quotations. I am not
sure that the subjects actually said, "Nothing," but they did report
that there were no effects. In my own experiments, my notes record
the phrase, "No effects whatsoever."
A little background: one of the transmitter
heavyweights in the brain
is called dopamine because it is an amine that
comes from an amino acid that is 3,4-dihydroxyphenylalanine
in German, is Di-Oxo-Phenyl-Alanine
, or DOPA. The levo-optical (or
of DOPA has rather cutely been called the punch-drunk
Spanish matador, or El Dopa. But that is not part of the story.
The story is really about the "Pink Spot of Schizophrenia
." Many years
ago, an observation was made in a biochemical
laboratory on the East
Coast that stirred up a rolling controversy. It had been found that
if the urines of schizophrenic
patients (sloppily called
urines") were extracted in such and such a way, and the
, a pink spot would develop at a particular
place on the chromatogram
. Well, if this proved to be true with
urines of a sick population, and were this proved to be different from
the urines of a healthy population, it would constitute an objective
diagnosis of schizophrenia. A simple chemical test to confirm a
pathology that had defied all efforts to achieve consensus amongst the
psychiatrists of the world.
The literature was suddenly filled with dozens of papers. Researcher
A confirmed that the pink spot was found with schizophrenic
s, and not
with normal controls. Researcher B found the pink spot in all urines,
regardless of pathology. Researcher C found it in no urines at all.
Researcher D argued that it was a factor from the hospital diet.
Researcher E found that the pink spot reflected the time of day that
the urine sample was collected. Researcher F drew a conclusion about
where truth might lie by tallying the number of papers that supported
argument A, B, C, D, or E.
The only confirmable fact that endured was that the pink spot was due
to DMPEA. So a bright spotlight was directed towards its possible
role in mental illness. And this expressed itself in the simple
question: would it produce schizophrenia in a normal subject? No.
And in a way I am comforted that that did not evolve into a simple
litmus test for a schizophrenic
diagnosis. There are so many
cultural, political, and social factors that come to bear on the
assignment of a diagnosis of mental illness, that I would have been
forever skeptical of a neat biochemical
A chemical modification of DMPEA that has been explored in this
question of pink spots, mental pathology, and diagnostic markers, is
the corresponding acetamide
. One of the metabolite
s of DMPEA was
found to be the N-acetyl
. It was found to be demethylated
in man, and
to have pharmacological
activity in animals. Maybe this was the
active compound that could be involved in the schizophrenic
But human trials with it, as with the principal metabolite
acid, showed nothing at all in man.
Another chemical modification is the beta-hydroxy analogue
It has been explored separately, and is the subject of its own recipe,
in its own rights. See DME.
Pink was not the only colorful spot associated with schizophrenia.
Somewhere at about this same time, a research paper from Canada
reported the observation of a mauve spot in the chromatographic
analysis of urines of schizophrenic
patients. This had nothing to do
with DMPEA. I was working closely with a researcher at the
institute and we were fascinated by, again, a possible
diagnostic marker. We assayed the urines of the next 10 patients
being admitted as acute schizophrenic
s. No trace of mauve. We wrote
, and verified the analytical
procedure. We were told that
the whatzis should have been added after, rather than before, the
whosey, and that we should have heated for 30, not 10 minutes. Okay.
We assayed the urines of the next 10 patients being admitted using
these new directions. No trace of mauve. Another call to Canada
we were informed that we still weren't doing it right. They were
consistently batting a 100% positive correlation between mauve spots
s, and 0% with healthy controls. In fact, they
actually gave this positive test the name of a disease, Malvaria.
Then, that little burst of insight! Aha! What if, just what if, they
had been seeing something given to their schizophrenic
Chlorpromazine was the popular treatment of the day. We took a
whopping dose of chlorpromazine
, and over the next couple of days did
manage (barely) to collect our urine samples. Both of us were
positive Malvarians! And three days later, we were again negative.
We were most likely seeing a metabolite
. One last
call to Canada
with the ultimate question--had you given any
medication to your schizophrenic
s before your urine analysis? Of
course (came the answer)--it would not be ethical
to leave them
untreated. Another color down the drain, and still no objective
measure for mental illness.
By the way, I cannot say I like the chlorpromazine
trip. There is no
real communication either with others or with yourself, with that
stuff. You are a zombie
, but if you are both schizophrenic
, you cannot possibly be troublesome for anybody in the
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