Phenylisopropylamines

Therapeutic Function Central stimulant Chemical Name (S)-a-methylbenzeneethanamine sulfate Common Name d-j3-phenylisopropylamine sulfate Structural Formula... 

Recent controversy about the recreational abuse and potential therapeutic use of designer drugs has focused attention on MDA (methylenedioxyampheta-mine HCl) and structurally related phenylisopropylamine compounds, including MDMA istructural analogs of the psychomotor stimulant amphetamine and the hallucinogen mescaline, and produce stimulant and/or hallucinogenic effects (Shulgin 1978). 

Glennon, R.A. Young, R. and Flank, A.E. Structure-activity studies on methoxyaubstituted phenylisopropylamines using drug discrimination methodology. Pharmacol Biochem Behav 22 723-729. 1985. 

Glennon, R.A. Discriminative stimulus properties of phenylisopropylamine derivatives. Drug Alcohol Depend 17 119-134, 1986. 

Glennon, R.A. Psychoactive phenylisopropylamines. In Meltzer, H.Y., ed. Psychopharmacology The Third Generation of Progress. New York Raven Press, 1987a. pp. 1627-1634. 

Lyon, R.A. Davis, K.A. and Titeler, M. H-DOB (4-bromo-2,5-emethoxy-phenylisopropylamine) labels a guanine nucleotide-sensitive state of cortical 5-HT2 receptors. J Pharmacol Exp Ther 31 194-199, 1987. 

Alles, G.A. The comparative physiological actions of the DL-beta-phenylisopropylamines. I. Pressor effect and toxicity. J. Pharmacol. Exp. Ther. 47 339, 1933. 

The synthetic applications of this reagent to the synthesis of nitroalkenes have been known since the 1960s.60 Nitration of alkenes with nitryl iodide, generated in situ from iodine and silver nitrite, is convenient for the synthesis of P-nitrostyrenes with various functional groups.61 This method is applied to the synthesis of ortho-methoxylated phenylisopropylamines, which are potent serotonine agonists (Eq. 2.31).62... 

TABLE 1. Human hallucinogenic potencies of 2,5-dimethoxy-4-substituted phenylisopropylamines ... 

Anderson, G. M., Ill, Castagnoli, N., Jr., and Kollman, P. A. (1978) Quantitative structure-activity relationships in the 2,4,5-ring substituted phenylisopropylamines. In NIDA Research Monograph Series 22, edited by G. Barnett, M. Trsic, and R. Willette, pp. 199-217. U. S. Govt. Printing Office, Washington, D. C. 

This view offers an explanation for the stereoselectivity of the phenylisopro-pylamines, i.e., the isomer that is more active is the one that presents least interference to the drug-receptor interaction. This idea would be consistent with the observation that the R enantiomers of the phenylisopropylamines have receptor affinity similar to their nonalpha-methylated homologs, and that the alpha-methyl of the S enantiomer of the amphetamines has a deleterious effect on affinity (72,78). There is no strongly compelling evidence in favor of either of the above hypotheses, however, and either is tenable. 

Either phenethylamine or phenylisopropylamine will work. If the hydrochloride salt is available, this should first be changed to the free amine by stirring with concentrated aqueous NaOH. 

O. 016 mole of the amine and then 3.6 g of formaldehyde (ca. 10 ml of formalin) and reflux for 5 hours. Cool to room temperature, add 7 ml concentrated HCI and evaporate in vacuum. The resulting oily dimethylamine can be purified by dissolving in 25 ml water, extracting with 2X25 ml CHCI3. Basify the aqueous layer with 2N NaOH and extract with 3X25 ml ether, and proceed as described above for the N-methylamines. This procedure should work for both phenethylamines and phenylisopropylamines, and should affect the trip similarly to N-monomethylation. 

For fenfluramine, MDMA and methysergide, in vivo oxidation gives rise to a more potent 5-HT2B receptor agonist than the parent compound. The oxidized nitrogen is indicated by a solid arrow. Note that all drugs fall into one of the two structural classes phenylisopropylamines (top) and ergolines (bottom). 

Titeler M, Lyon RA, Glennon RA. (1988). Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology (Berlin). 94(2) 213-16. 

Phenylisopropyl-hydroxylamine can be reduced to phenylisopropylamine as follows A solution of 6g (0.04 mole) of phenylisopropyl-hydroxylamine in 80 ml of absolute ether is treated with 1.9 g (0.05 mole) of LAH in 150 ml of absolute ether in the usual manner and refluxed for an additional hour. After cooling, a sample of the reaction mixture should give a positive Gilman-Shulze color test, indicating an excess of the hydride (this test is not necessary for you to perform). Hydrolysis was carried out with 400 ml of 20% aqueous sodium potassium tartrate and after separation of the layers, the aqueous portion is extracted with two additional 75 ml volumes of ether. Rectification yields 2.0 g of substituted phenylisopropylamine. JACS, 1837 (1952). 

Note According to Merck and Co., the potency of the hydroxy version of phenylisopropylamine is nearly as great as the non-hydroxy version, thus the above reduction may be omitted if you find the phenylisopropyl-hydroxylamine high enjoyable. Hydroxy methylenedioxyphen-ethylamine has been reported to be a very pleasant high. 

To a solution of 40.5 g of the above aldehyde and 16 g of nitromethane (for mescaline) or an equimolar amount of nitroethane (for phenylisopropylamines) in 100 ml of ethanol, add 14 ml of 3% methylamine in methanol, in nitrogen atmosphere if possible. Let stand at room temp for one day, then cool to -10°, filter, wash with cold methanol, and evaporate the solvent in vacuo to get the nitrostyrene or nitropropene. 

Substitutions at the a carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of -substituted compounds (Figure 9-5). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body they are indirectly acting sympathomimetics. 

Ephedrine occurs in various plants and has been used in China for over 2000 years it was introduced into Western medicine in 1924 as the first orally active sympathomimetic drug. It is found in ma huang, a popular herbal medication (see Chapter 64). Ma huang contains multiple ephedrine-like alkaloids in addition to ephedrine. Because ephedrine is a noncatechol phenylisopropylamine (Figure 9-... 

Amphetamine is a racemic mixture of phenylisopropylamine (Figure 9-4) that is important chiefly because of its use and misuse as a central nervous system stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine however, amphetamine even more... 

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