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A series of 2-amino-1-(4-substituted-2,5-dimethoxyphenyl)butanes (Table V) was prepared as analogues of (R)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane (1a). 1-(2,5-Dimethoxyphenyl)-2-(N-phthalimido)butane (7) was utilized as a synthetic intermediate common to many of the target compounds. Animal data are presented indicating that most of these analogues have low hallucinogenic potential. Selected compounds were compared with 1a in an avoidance-response acquisition model which differentiates between 1a and the human hallucinogens DOM (2a) and DOET (2b). Structure-activity relationships of these analogues are discussed.

2-Amino-5,8-dimethoxy-6-methyl-l,2,3,4-tetrahydronaphthalene and 2-amino-4,7-dimethoxy-5-methylindan were prepared as rigid analogs of psychotomimetic phenylisopropylamines. Neither compound appeared to have psychotomimetic activity in rats. The effect of the aminotetralin derivative on 5-HT receptors in rat fundus strips and sheep umbilical arteries was also studied.

Alicyclic structures carrying alkylamine chains have been the subject of a number of pharmacodynamic studies,1-3 especially for their effect on blood pressure. By comparison with their aromatic prototypes, such alicyclic compounds show less activity and higher toxicity.2 Cyclohexenyl, cyclohexyl and cyclopentyl derivatives were of the same general order of lowered activity.Branching of the side chain increased duration of action, in analogy with similar effects of 2-phenylisopropylamines as compared with those of phenethylamines.These observations acquired renewed significance in the wake of Belleau's proposal4 of a working model of an adrenergic receptor site which emphasized the importance of van der Waals bonds in reinforcing the ionic linkage between the amino group and an anionic site. Obviously, a flat benzene ring may be expected to furnish a supporting attachment of 2-3 kcal/mole while a puckered, non-aromatic ring will be of much less value as a source of shortrange bonds. Three factors should influence the magnitude of these forces: (a) the size of the ring; (b) the planarity of the ring; and (c) the angle between the substituent chain and the ring. In the present work, the amino alcohols II-V were tested and compared with phenylethanolamine (I). The pressor activity of these compounds increases in the order V < IV s III < II < I.