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#60 DMPEA
3,4-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: A
solution of 33 g
3,4-dimethoxybenzaldehyde in 140 mL
acetic acid was treated with 23 mL
nitromethane and 12.5 g
anhydrous
ammonium acetate, 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 that
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 tem
perature,
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 was brought
to >9, and the clear
solution was extracted with 3x100 mL
CH2Cl2.
Remo-val of the
solvent from the combined extracts under vacuum gave
5.2 g of a pale yellow oil. This was
dissolved in 300 mL
anhydrous
Et2O and saturated with
anhydrous HCl gas, giving 5.0 g of a slightly
sticky off-white solid. This was re
crystallized from 75 mL of boiling
CH3CN to give 3.3 g
3,4-dimethoxyphenethylamine hydrochloride (DMPEA)
as beautiful white
crystals.
DOSAGE: greater than 1000 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (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
metabolite of DMPEA) RNothing.
(with 500 mg of N-
acetyl-
3,4-dimethoxyphenethylamine, a major human
metabolite of DMPEA) RNothing.
EXTENSIONS AND COMMENTARY: Why all the interest? Why keep pursuing a
compound that is so obviously without activity? Or a
metabolite that
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 dop
amine.
Dopamine is called dopamine because it is an amine that
comes from an amino acid that is
3,4-dihydroxyphenylalanine and this,
in German, is Di-Oxo-Phenyl-
Alanine, or DOPA. The levo-optical (or
L-)
isomer 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
"
schizophrenic urines") were extracted in such and such a way, and the
extracts
chromatographed, 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
schizophrenics, 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 marker.
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
metabolites of DMPEA was
found to be the N-
acetyl deriva-tive, N-acetyl-3,4-
dimethoxyphenethylamine. 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 process.
But human trials with it, as with the principal
metabolite
3,4-dimethoxyphenylacetic acid, showed nothing at all in man.
Another chemical modification is the beta-hydroxy
analogue of DMPEA.
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
psychiatric institute and we were fascinated by, again, a possible
diagnostic marker. We assayed the urines of the next 10 patients
being admitted as acute
schizophrenics. No trace of mauve. We wrote
to
Canada, 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, and
we were informed that we still weren't doing it right. They were
consistently batting a 100% positive correlation between mauve spots
and
schizophrenics, 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
schizophrenics?
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 of
chlorpromazine. One last
call to
Canada with the ultimate question--had you given any
medication to your
schizophrenics 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 and a
zombie, you cannot possibly be troublesome for anybody in the
emergency room.
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