SYNTHESIS : A solution of 4.78 g
2-methylindole-3-carboxaldehyde in 18 mL of nitroethane was treated
with 0.77 g anhydrous ammonium acetate and heated on the steam bath
for 2 h. The excess nitroethane was removed under vacuum and the
residual orange-red solids were removed and washed with H2O. After
drying these were triturated under 25 mL MeOH, filtered and air-dried
to constant weight. There was thus obtained 3.8 g (59%) of
1-(2-methylindol-3-yl)-2-nitropropene with a mp 146-148 °C.
To 250 mL of a room-temperature 1.0 M solution of LAH in THF, well
stirred and under N2, there was added a saturated solution of 3.6 g
1-(2-methylindol-3-yl)-2-nitropropene in warm THF. The addition took
place over 1.25 h, the reaction mixture was stirred for an additional
8 h, and then held at 40 °C for 8 more h. The slurry was then
cooled in an ice bath and decomposed by the slow, sequential addition
of 30 mL isopropyl acetate, 20 mL H2O and, finally, 20 mL of 20%
aqueous NaOH. The resulting alkaline suspension was extracted with
3x100 mL isopropyl acetate. The extracts were pooled, washed with 3x50
mL 10% aqueous NaOH, then extracted with 10% aqueous acetic acid. This
extract was washed with isopropyl acetate, made basic with 20% aqueous
NaOH, and extracted with 3x50 mL CHCl3. These extracts were pooled,
dried with anhydrous Na2SO4 and, after removal of the drying agent by
filtration, the solvent was removed under vacuum. The residual yellow
oil was distilled under vacuum, at 150-160 °C at 1.8 mm/Hg, to give
a pale yellow product. This was dissolved in a few mL MeOH and
neutralized with a solution of fumaric acid in MeOH. The clear
solution was heated and diluted with two volumes of hot isopropyl
acetate. On cooling, fine white crystals of a,2-dimethyltryptamine
fumarate (2,a-DMT) were deposited. These were removed by filtration,
and air-dried to constant weight. The yield was 1.64 g (60%) of a
product with a mp of 209-211 °C.
DOSAGE : 300 - 500 mgs
DURATION : 7 - 10 hrs
QUALITATIVE COMMENTS : (with 200 mgs, orally) "I feel just a
little bit intoxicated. Probably few if any effects."
(with 300 mgs, orally) "It was an hour before I realized that
something was happening. Very subtle, some tingling of the face, the
lights are somehow brighter. Really laid back, try to let my fantasy
go with closing my eyes and sitting quietly, but it mostly just felt
good to sit quiet. I feel that I am on the edge of something here, but
I see it slipping away. "
(with 450 mgs, orally) "It was almost as if I had had a drink too
many. I was feeling good, but I tried turning the dial on the radio to
find music, and the fine motor coordination in my hands was not
there. My thinking was completely clear, and the music I finally found
was fine for day-dreaming. There were some flashes on the edge of my
visual field and things seemed to feel softer and richer. Eating was a
quite an adventure in tastes, but I really couldn't eat much. Very
peaceful, and an easy sleep took over at about the 13th hour. Next
day, still pretty dehydrated. All in all, it was a very nice
experience."
EXTENSIONS AND COMMENTARY : I do love the satisfying feeling
that comes with the successful assignment of a pharmacological change
as a function of a single structural change. This is the holy grail of
every SAR enthusiast (SAR = Structure Activity Relationship). Make a
change in structure, see a corresponding change in activity. There is
a correlation. There is causality. And there you have a new, firmly
established fact of science to add to the understanding of the
universe.
A case in point. What happens when you put a methyl group on the
two-position of the indole ring of a tryptamine. In the three
examples, examples of the best studied tryptamines that were not
active orally, they all became orally active. DMT, DET and 5-MeO-DMT,
the three major parenterally-only active psychedelics, all blossomed
into orally active compounds with the addition of a simple methyl
group to that indole 2-position. As I had smugly argued, in the
discussions of 2-Me-DMT, 2-Me-DET and Indapex, it is as if that bit of
bulk got in the way of the destructive amine oxidases, and protected
the molecule from its expected first-pass metabolic destruction.
So what happens here? You take a compound, a-MT, that is already
immune to this oxidase system and is already orally active. Add a
2-methyl group to give 2-Me-a-MT, or 2,a-DMT. And what happens? The
potency goes down, not up, and by a factor of 10 times. And it ends up
being more of a sedative than a stimulant. So much for generalities. I
suspect that I do not understand the universe nearly as well as I
thought I did.
