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A homologous series of 4-alkyl-2,5-dimethoxyphenylisopropylamines (alkyl = H through n-C5H11 and t-C4H9) was synthesized and compared with mescaline as serotonin agonists in a sheep umbilical preparation. The three-carbon homolog 6d was found to be the most potent of the straight-chain series in accordance with its observed psychotomimetic effectiveness in man.

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The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (4) were prepared from the chiral 2-[(tosyloxy)methyl]-1,4-benzodioxanes [(2S)- and (2R)-5]. The corresponding (2R)- and (2S)-2-(aminoethyl)-1,4-benzodioxanes [2R)- and (2S)-7] were prepared by a modified Gabriel synthesis and converted to the enantiomers of 4 by condensation with 2,6-dimethoxyphenoxyacetaldehyde (8) and reduction of the intermediate imine with NaBH4. The enantiomer (2S)-4 was 40--50 times as potent as the enantiomer (2R)-4 in antagonizing the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips, showing a pA2 = 9.0. This result is consistent with the previous observation that S enantiomers of 2-[(alkylamino)methyl]benzodioxanes are more potent antagonists at a alpha-adrenergic receptors than the R enantiomers.

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.

Replacement of the 4-methoxy of mescaline with higher alkyl homologues or with bromine led to increased activity at serotonin receptors in a sheep umbilical artery preparation. This activity appears correlated with lipophilicity, as measured by 1-octanol-water partition coefficients, but drops off when the 4-substituent is about five atoms in length. It is suggested that 3,4,5-trisubhe 2,4,5-substitution pattern.