[www.rhodium.ws] [] [Chemistry Archive]
 
 

Psychotomimetic Agents Related to Mescaline

Alexander T. Shulgin
Experientia 19, 127-128 (1963)

HTML by Rhodium

The widely studied pharmacology of mescaline (I; R = H) and the recent descriptions of the psychotomimetic effects dl-trimethoxyamphetamine1,2 (I; R = CH3) have prompted the synthesis of higher homologs (I; R = C2H5 through C7H15). All of the amines were prepared by the LiAlH4 reduction3 of the corresponding nitrostyrenes, which were in turn prepared (with the exception of the nitropropane isomer mentioned below) by the ammonia-catalyzed condensation of the appropriate nitroalkane with 3,4,5-trimethoxybenzaldehyde, in acetic acid.

With nitropropane in acetic acid, the solid product was identified as 3,4,5-trimethoxybenzonitrile4, and substitution of isopropyl alcohol for the acidic solvent led to unexpected formation of the Schiff base II, mp 151.5-152C from methanol, the structure of which was established by analysis and its facile acid hydrolysis to trimethoxybenzaldehyde and, after neutralization, 1-(3,4,5-trimethoxylphenyl)-2-nitrobutylamine. Replacement of the ammonia catalyst with a secondary amine precluded the formation of II, and led to a proper nitrostyrene. The properties and yields of the substances studied appear in the Table.

R
Nitrostyrenesa
Phenethylamines
mp
Yield
mp (picrate)
mp (HCl)
Yield
-H
120-121Cb
64%
214-216°C
180-181°C
86%c
-CH3
93-94Cd
50%
171-173°C
208-209Ce
62%
-CH2CH3
72-73°C
29%
177-181°C
192-193°C
52%
-(CH2)2CH3
82.5-83.5°C
32%
182-184°C
214-218°C
65%
-(CH2)3CH3
73-74°C
34%
168-170°C
182-184°C
45%
-(CH2)4CH3
54-55°C
24%
162-163°C
155-158°C
50%
-(CH2)5CH3
51-52°C
21%
149-151°C
132-134°C
53%
-(CH2)6CH3
43-44°C
19%
148-149°C
112-116°C
19%
-(CH2)8CH3
46-47°C
16%
-
-
-
  1. All listed compounds were yellow crystalline solids,
    recrystallized from methanol.
  2. Literature values are reported from 118 to 121C.
    It was found that if the molten material was held at this
    temperature for a short period, resolidification occurred
    yielding a new crystal form with a melting point 128-129C.
  3. Literature value included for comparison, see 3.
  4. Literature value 95C, see
    P. Hey, Quart. J. Pharm. Pharmacol. 20, 129 (1947)
  5. Literature value 219-220C, see above reference.

Toxicity and behavioral studies with mice could not distinguish between the first three members of this series. For all, LD50's were established to be between 200-300 mg/kg, i.p., and at 80 mg/kg there was the mild, agitated behavior previously described1; complete recovery occurring within 8 h.

In human subjects, the potency of trimethoxyamphetamine (I, R = CH3) has been established as over twice that of mescaline2. Evaluation of the immediate homologue, α-ethyl mescaline (I, R = ethyl) at oral levels in excess of 2.5 mg/kg (as the free base), produced neither central activity nor psychic disturbance, thus demonstrating a psychotomimetic potency of less than half that of trimethoxyamphetamine, and suggesting that three carbons represent an optimum chain length.

References

  1. D. I. Peretz, J. R. Smythies, and W. C. Gibson, J. Ment. Sci. 101, 317329 (1955)
  2. A. T. Shulgin, S. Bunnell, and T. Sargent III, Nature 189, 1011 (1961)
  3. F. A. Ramirez and A. Burger, J. Amer. Chem. Soc. 72, 2781 (1950)
  4. H. M. Blatter, H. Lukaszewski, and G. DeStevens, J. Amer. Chem. Soc. 83, 2203 (1961)