SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of
2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated
gradually to about 150 °C with an open flame. A single clear phase
was formed with the loss of H2O. After the hot melt remained quiet
for a few moments, it was allowed to cool to about 50 °C and then
diluted with 100 mL of hot MeOH. The solution was stirred until
homogenous, seeded with product, and then cooled in an ice bath to
complete the crystallization. After removal of the product by
filtration, washing sparingly with MeOH, and air drying, there was
obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as
off-white crystals, with a mp of 105-106 °C. Anal. (C19H19NO4) C,H,N.
To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide
in 15 mL warm acetic acid which was being vigorously stirred, there
was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid.
This was stirred for 2 h at about 40 °C during which time there was a
definite lightening of color, but no solids formed. The reaction
mixture was poured into 600 mL H2O which produced a reddish glob
floating in a yellow-orange opaque aqueous phase. The glob was
physically removed, dissolved in 30 mL boiling MeOH which, on cooling
in an ice bath, deposited off-white crystals. These were removed by
filtration, washed with MeOH, and air dried to give 1.5 g of
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide as fine white
crystals with a slight purple cast. The mp was 103-105.5 °C and the
mixed mp with the starting non-iodinated phthalimide (mp 105-106 °C)
was depressed (85-98 °C). Extraction of the aqueous phase, after
alkalinification, provided an additional 0.15 g product. Anal.
(C19H18NO4) C,H,N.
A solution of 0.75 g
N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide in 10 mL EtOH
was treated with 0.3 mL of hydrazine hydrate, and the clear solution
was held at reflux on the steam bath overnight. After cooling, there
was a crystallization of 1,4-dihydroxyphthalizine that started as
small beads but finally became extensive and quite curdy. These
solids were removed by filtration and had a mp of about 340 °C
(reference samples melted over a five to ten degree range in the area
of 335-350 °C). The filtrate was dissolved in 100 mL CH2Cl2 and
extracted with 2x150 mL 0.1 N HCl. The aqueous extracts were washed
once with CH2Cl2, made basic with 5% NaOH, and extracted with 3x100 mL
CH2Cl2. Removal of the solvent under vacuum gave 0.5 g of a colorless
oil which was dissolved in 300 mL anhydrous Et2O and saturated with
anhydrous HCl gas. There was obtained, after filtration, and air
drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)
as white crystals that melted at 200.5-201.5 °C. This value did not
improved with recrystallization. Anal. (C11H17ClINO2) C,H,N.
DOSAGE: 1.5 - 3.0 mg.
DURATION: 16 - 30 h.
QUALITATIVE COMMENTS: (with 0.6 mg) There was a nice spacey
light-headedness for a few hours, and time seemed to move quite
slowly. Then a generic sadness came over me, as I reminisced about
earlier days (recalling pleasures now gone) and wondered if I would be
allowed to be here on the Farm when I am old and not important. There
is so much to be done, and I cannot do it all, and no one else cares.
My mood became present-day and healthy by about the seventh hour.
(with 1.6 mg) The general nature of the experience was depressing,
with a sad view of life. There was no way I could connect with my
emotions. Even my sadness was vague. At about the ninth hour I
decided that enough was enough, and this strangely disappointing
about-plus-two was aborted with 125 micrograms of LSD. The emotions
became present and living within a half hour. I was greatly relieved.
The erotic was not a mechanical attempt but a deeply involved feeling
with an archetype of orgasm easily available. It was shaped like a
flower, richly colored, with an unusual "S" shape to it. This was a
lovely end to a difficult day.
(with 3.0 mg) This is a clear, clean psychedelic. The eyes-closed
imagery is excellent, with clearly delineated patterns, pictures, and
colors. Perfect for an artist, and next time I'll devote some time to
painting. Total ease for the body, but no help for my smoking
problem. I still want to smoke. And at sixteen hours into this I am
still at 1.5+ but I'll try to go to bed anyway, and sleep.
(with 3.5 mg) I was at a full crashing +++ for about three or four
hours. There was none of the LSD sparkle, but there were moments of
`light-headedness' where one could move sideways with reality. I
could leave where I was right over there, and come over here and get a
strange but authentic view of where the `there' was that I had left.
It would be out-of-body, except that the body came over here with me
rather than staying there. This doesn't make sense now, but it sure
did then. There was no trace of body impact, and I slept late that
evening, but with some guardedness due to the intense imagery. This
was no more intense than with 3.0 milligrams, but it was a little bit
more to the unreal side.
(with 1.0 mg of the "R" isomer) There was a clear ++ from the second
to the eighth hour, but somehow there was not quite the elegance or
the push of the racemate. I was sensible, and managed to do several
technical chores in a reasonable way. Easy sleep at 15 hours into
it.
(with 2.3 mg of the "R" isomer) The water solution of the
hydrochloride salt has a slightly sweetish taste! I was at a +++
without question, but there was a slight down mood towards the end.
And it lasted a really long time; I was distinctly aware of residual
stuff going on, well into the next day.
(with 6.3 mg of the "S" isomer) I was at a benign one-and-a-half plus
at about two hours, and finally flattened out at a ++. Would I double
this dose? Probably not, but half again (to 9 or 10 milligrams) would
feel safe for a plus 3. By evening I was near enough baseline to
drive into town for a social obligation, but even when trying to sleep
later that night there was some residue of imagery; remarkably, it was
all in slow motion. The fantasies were slow-paced and sluggish. It
would have been interesting to have explored eyes-closed during the
day.
EXTENSIONS AND COMMENTARY: Again, as with every other psychedelic
amphetamine analogue which has a chiral center and has been explored
as the individual optical isomers, it is the "R" isomer that is the
more potent. And again, the other isomer, the "S" isomer, still shows
some activity. The same was true with DOB, and DOM, and MDA. The
only exception was MDMA, but then that is more of a stimulant, and
there is virtually no psychedelic component to its action. Rat
studies, where there is a measure of the discrimination of a test
compound from saline, have shown the "R" isomer to have about twice
the potency of the "S" isomer. That the "R" is more potent is
certain, but the above reports would suggest that the factor would be
closer to times-four rather than times-two.
A number of studies with DOI in animal models have shown it to have an
extremely high binding capacity to what are called the 5-HT2
receptors. Serotonin is a vital neurotransmitter in the brain, and is
strongly implicated in the action of all of the phenethylamine
psychedelics. The place where it acts, at the molecular level, is
called its receptor site. As an outgrowth of the cooperative studies
of the medicinal chemists working closely with the
neuropharmacologists, a number of compounds have emerged that interact
with these sites. But this one interacts with these sites and not
those, and that one interacts with those sites and not these. So,
there has developed a collection of sub-divisions and sub-subdivisions
of receptor sites, all related to serotonin, but each defined by the
particular compound that interacts most tightly with it.
Thus, there were serotonin "1" receptors, and then there were "1" and
"2" receptors, and then "1a" and "1b" and "2a" and "2b" receptors, and
on and on. These are called 5-HT receptors, since the chemical name
for serotonin is 5-hydroxytryptamine, and the scientist would never
want to let the layman know just what he is talking about. DOI has
been synthesized with a variety of radioactive iodine isotopes in it,
and these tools have been of considerable value in mapping out its
brain distribution. And by extrapolation, the possible localization
of other psychedelic compounds that cannot be so easily labelled. A
small neurochemical research company on the East Coast picked up on
these properties of DOI, and offered it as a commercial item for
research experiments. But I doubt that they are completely innocent
of the fact that DOI is an extremely potent psychedelic and that it is
still unrecognized by the Federal drug laws since, in their most
recent catalog, the price had almost doubled and a note had been added
to the effect that telephone orders cannot be accepted for this
compound.
The four-carbon butylamine homologue (the ARIADNE analogue) of DOI has
been synthesized. A mixture of the free base of
1-(2,5-dimethoxyphenyl)-2-aminobutane (see preparation under DOB) and
phthalic anhydride was fused, cooled, and recrystallized from either
methanol or cyclohexane to give crystals of
N-[1-(2,5-dimethoxyphenyl)-2-butyl]phthalimide with a melting point of
76-77 °C and an analysis (C20H21NO4) C,H,N. This was iodinated with
iodine monochloride in acetic acid to give
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-butyl]phthalimide which was
chromatographically distinct from the uniodinated starting material
(silica gel, CH2Cl2 ), but which did not crystallize. This was
treated with hydrazine hydrate in ethanol to provide
1-(2,5-dimethoxy-4-iodophenyl)-2-aminobutane hydrochloride which was
crystallized from CH3CN/EtOH to give white crystals with a mp of
217-218.5 °C and an analysis (C12H19CINO2) C,H,N. This butyl homolog
of DOI has been assayed at up to four milligrams, and is without any
central effects whatsoever. An experiment with 12.4 microcuries of
131I labelled material with the whole body scanner showed most of it
accumulating in the gut and liver, with almost none to the brain.
For those who find such statistics interesting, the parent compound
DOI vies with DOB as probably the most potent of the phenethylamine
psychedelics as of the moment, and certainly one of the most long
lived.
A very important, centrally pivotal, and completely paradoxical
compound in this area, is the N,N-dimethyl homologue of DOI, or
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA). This compound
was the starting point of the study of a large number of homologues
and it deserves, and has received, a separate recipe.
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