2-Phenethylamines structure-activity relationships

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. 

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. 

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. 

Hansch and Caldwell have analyzed the quantitative structure/activity relationships (QSAR) of a series of amphetamine and 2-phenethylamine analogs, to discern the role of steric and hydrophobic aryl substituents on the inhibition of 5-HT uptake (142). From the biological data of 19 compounds, including those in Table 15.13. and some additional analogs, the following equation was derived for inhibition of uptake activity, where C is the IC concentration, MR4 is the molar refrac-tivity value of the aryl substituent scaled by 0.1, and 7T3 is the hydrophobicity of the meUi substituent on the aryl ring ... 

Non-Phenethylamine Derivatives - The search for compounds which bear no structural relationship to phenethylamlnes and have anorectic properties continues. Current studies on Wy-5244 (XIV) show it to possess only weak sympathomimetic activity in isolated cat atria and rabbity aortic strips however the compound apparently does alter adrenergic receptor mechanisms since the actions of substances such as norepinephrine, d-amphetamine, phenoxybenzamine, and Imlpramine were profoundly influenced by Wy-5244.31 The synthesis of (XIV) and related compounds has been described.32... 

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