TiHKAL #46 5-MES-DMT

CHEMISTRY :To a solution of 5.0 g of 5-methylthiotryptamine as the free base (the hydrochloride, with mp 252-254 °C or 263-265 °C, is dissolved in H2O, made basic with aqueous NaOH, extracted with CH2Cl2, and the solvent removed under vacuum) in 250 mL MeOH, there was added 4.0 g NaHCO3 and 6.8 g MeI. This was held at reflux for 72 h, with the addition of 1.5 g more MeI at both the 24 and the 48 h time. Removal of the volatiles under vacuum produced a white residue which was dissolved in 300 mL boiling EtOH, insolubles removed by filtration of the hot solution, and the filtrate allowed to cool. Fine white crystals appeared which were removed by filtration, and air-dried to produce 3.22 g (53%) of 5-methylthio-N,N-dimethyltryptamine methiodide with a mp 177-179 °C.

A suspension of 3.00 g 5-methylthiotryptamine methiodide in 50 mL DMF was treated with 1.9 g 1,4-diazobicyclo[2.2.2]octane and held at reflux for 3 h. The reaction mixture was diluted with 300 mL H2O, extracted first with 200 mL EtOAc followed by 400 mL benzene. These extracts were combined and back-extracted with 10% HCl. This aqueous phase was made basic with 5N NaOH, and extracted with several portions of EtOAc. The organic extracts were pooled, dried with MgSO4, and the solvent removed under vacuum to give a residue that was a dark gold oil. This was distilled at the KugelRohr to give a fraction that boiled at 130-140 °C at 0.01 mm/Hg that was a yellow solid, with mp 94-97 °C. This was recrystallized from benzene/petroleum ether to give 1.41 g (76%) 5-methylthio-N,N-dimethyltryptamine as colorless needles, with a mp 97-100 °C.

QUALITATIVE COMMENTS :(15 mg, smoked) "Consumed it over 75 seconds, 15 seconds later I noticed it. Light, no visual, rather pointlessly stoned. In another 5 minutes I am starting to clear, and in another 5 I am repaired."

(with 20 mg, smoked): "Coming on very fast, quite intense, and within half an hour I am clear. I suspect 30 mg would be effective."

EXTENSIONS AND COMMENTARY : Sulfur lies in the very same column of the periodic table as oxygen, in the location directly below it. Therefore there are many similarities as to chemical bonding, making things like thioethers that are true analogues of ether. A sulfur atom between two carbons rather than an oxygen atom. Bit, the polarity, and lipophilicity properties are different and the pharmacology is, of course, different. In the phenethylamine series, as reported in PIHKAL, there can be a considerable increase in potency. With the basic skeleton of 2,5-dimethoxyamphetamine, the replacement of a 4-methoxy group (giving TMA-2, active level 20-40 milligrams) with a 4-methylthio group (giving Aleph-1, active level 5-10 milligrams). The corresponding change for the ethyl counterparts (from MEM to Aleph-2) is an increase from an active level of 20-50 milligrams to one of 4-8 milligrams.

The 5-position on the indole ring of the tryptamine family is analogous to the 4-position in the phenethylamine family. And yet, here, with the 5-methoxy group of 5-MeO-DMT being replaced with the 5-methylthio group of 5-MeS-DMT, the activity actually seemed to decrease by a factor of two. Is this a generality of the tryptamines, or is this an anomaly of this one pair of compounds?

There is the raw stuff potentially available to answer this question. There are a couple of compounds known with the sulfur in the 4-position, which is the location of the oxygen atom in psilocybin. The 4-thio analogues have been synthesized from 4-methylthio-indole, via the oxalyl chloride method and reaction with the appropriate amine. With dimethylamine, the indoleglyoxylamide was made in a 43% yield and had a mp 163-164 °C. With diisopropylamine, the amide was made in a 27% yield and had a mp 190-192 °C. The final amines were prepared by the reduction of these amides with LAH in THF. N,N-Dimethyl-4-thiotryptamine (4-MeS-DMT) was obtained in a 68% yield and melted at 108-110 °C; N,N-diisopropyl-4-methylthiotryptamine (4-MeS-DIPT) was obtained in a 61% yield and melted at 92-94 °C. In animal studies of behavioral disruption with these three compounds, there was systematic drop of potency in going from the 5-MeS-DMT to 4-MeS-DMT to 4-MeS-DIPT.

The challenge would be to see what the activities would be in man. And, of course, to make a direct comparison to the oxygen counter-parts. The 5-MeO-DMT has already been mentioned, and the remaining two would be 4-MeO-DMT and 4-MeO-DIPT. The former is a known compound but has not been measured in man. The latter is not a known compound.

#46. 5-MES-DMT