Phenethylamines structure

The structural requirements of the dopamine (and norepinephrine) transporter appear to be fairly rigid. There is very little molecular variation that is tolerated without significant loss of activity. The relatively limited information that is available, mostly from animal studies, can be summarized by considering the various areas of substitution for a general phenethylamine structure. These structure-activity relationships have been recently surveyed (132), and an extensive and comprehensive review by Biel and Bopp (133) covered the older literature. 

The ability of 1-benzylated THI (5) to inhibit both DA and 8-receptors has been attributed to the existance of two phenethylamine structures that can provide both gauche (6) and trans (7) conformations20. 

The (3-phenethylamine structure is subject to MAO oxidation. The addition of an alkyl (usually CH3) substituent on the a-carbon confers considerable resistance to this enzyme on the molecule. This both prolongs the indirect peripheral and (3 adrenergic actions of these compounds, and results in considerable CNS stimulant properties. 

T. Fujita and T. Ban, Structure-activity study of phenethylamines as substrates of biosynthetic enzymes of sympathetic transmitters. J. Med. Chem., 14 (1971) 148-152. 

MDMA is believed to have unique psychoactive properties that clearly distinguish it from hallucinogenic or psychostimulant phenethylamines. Not only have MDMA users consistently reported this distinctiveness, but subsequent studies of MDMA and similar compounds, in many laboratories, have shown that they do not fit within the structure-activity relationships that presently are understood to define the hallucinogenic amphetamines. 

Shulgin, A.T. Psychotomimetic drugs Structure-activity relationships. In Iversen, L.L. Iversen, S.D. and Snyder, S.H., eds. Handbook of Psychopharmacology. Vol. 11. New York Plenum, 1978. pp. 243-333. Shulgin, A.T., and Carter, MF. Centrally active phenethylamines. 

Characteristic of its amphetamine-like structure, MDMA is a potent monoamine-releasing agent as demonstrated both in vitro (Nichols et al. 1982 Johnson et al. 1986 Schmidt et al. 1987) and in vivo (Yamamoto and Spanos 1988). This release occurs through a carrier-mediated, Ca -independent mechanism typical of the phenethylamines (Schmidt et al. 

Alternatively, competitive ELISA can be used to estimate the hapten density if an antibody that specitically recognizes the hapten is available. At first observation this approach seems circular because the immunoassay developed is used to determine hapten density on proteins used for immunization. However, if a small molecule mimic of the protein conjugate is used as a standard, the method can be accurate. For example, a hapten containing a carboxylic acid can be coupled to phenethylamine or tyramine, its structure confirmed and the material used to generate a calibratron curve to estimate hapten density. 

The 2-phenylcyclobutylamines Structures 14 and 15 have also been prepared (161). In contrast to the cyclopropylamine, however, 15 showed no clinical activity following oral administration of a dose up to 25 mg of the racemic hydrochloride (199). The trimethoxy congener 14 has not been tested. The appropriately ring-substituted tran.s-2-phenylcyclopentyl or cyclohexylamines have not been reported. Based on the apparent lack of activity for 15, as well as the lack of activity for alpha-ethyl phenethylamine derivatives, however, these might be predicted to be inactive. 

Vasko, M. R., Lutz, M. P., and Domino, E. F. (1974) Structure activity relations of some indolealkylamines in comparison to phenethylamines on motor activity and acquisition of avoidance behavior. Psychopharmacologia, 36 49-58. 

While mescaline is a simple 2-phenethylamine derivative, the addition of an alpha-methyl group to the side chain yields Structure 8 (TMA). This simple hybrid of the structures of mescaline and amphetamine retains the hallucinogenic effects of mescaline but possesses about twice the potency of the latter (174,200). Addition of the alpha-methyl to other 3,4,5-substituted compounds generally brings about an approximately twofold increase in potency. The addition of an alpha-methyl to 2,4,5-substituted compounds, however, may dramatically increase activity. For example, 2-(2,4,5-trimethoxyphenyl) ethylamine apparently is clinically inactive (195). Addition of an alpha-methyl gives TMA-2 (Table 1), with 20 times the potency of mescaline. However, the addition of an alpha-methyl does not significantly increase in vitro receptor affinity in either 3,4,5-or 2,4,5-series (72,78). Thus it is probable that the alpha-methyl may confer metabolic stability in vivo. It could also be speculated that this protection is more important in the 2,4,5-substituted series than in 3,4,5-substituted compounds. 

FIGURE 4.32 Structures of the MAO-A substrates (serotonin, norepinephrine), their deaminated metabolites, and its selective inhibitor, clorgyline, as well as the structures of the MAO-B substrates (/3-phenethylamine, trytamine), their deaminated metabolites, and its selective inhibitors, deprenyl and pargyline. 

Sasha had recently published his critically acclaimed PIHKAL, a Chemical Love Story ( Phenethylamines I Have Known and Loved. ). A lengthy book, the first part deals with his personal history and love affair with Ann. The second part is a technical compendium of the various psychedelic compounds he had developed. It includes structures, methods of synthesis and subjective effects as recorded by a group of special friends, who visited periodically to evaluate personally the latest of his psychoactive molecules. 

Phenethylamine is structurally related to a number of psychedelics, including mescaline. It also occurs in chocolate and is thought to be one of the substances responsible for the feel good effect of chocolate (other molecules contribute as well, including theobromine). Chocoholics will understand. 

There is no way to meaningfully extrapolate from this phenethylamine analogue 2,3-MDA to 4,5-MDO-DIPT, but it does present a very close structural relationship that could be used to justify a clinical study of this unusual tryptamine. 

These are the exact rings. They are easy to make they add a sense of sophistication to an otherwise pedestrian scientific paper and they often represent the inactive extremes in a receptor site study of a structure activity relationship study of a CNS-active agent. But the compounds represented here appear to have simply the wrong properties, somehow, and should not really be seriously considered in the quest for understanding of the remarkable actions of most of the psychedelic phenethylamines and tryptamines. 

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