Serotonin receptor affinities of psychoactive phenalkylamine analogs

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Abstract
Employing a rat fundus model, the serotonin (5-HT) receptor affinities of 45 phenalkylamine analogs were determined. Phenethylamine and phenylisopropylamine possess relatively low receptor affinities; in general mono-, di-, and trimethoxylation enhance affinity. Of the disubstituted compounds, methoxyl groups at the 2 and 5 positions are optimal for imparting a high affinity. 4-Methylation, 4-ethylation and 4-bromination enhance receptor affinity, while N,N-dimethylation of the terminal amine decreases affinity. .alpha.-Methylation of phenethylamines had little effect on affinity when racemates are examined. Introduction of a benzylic keto group can increase or decrease affinity, depending upon the presence of other aromatic substituents. The most behaviorally active compounds possessed the highest 5-HT receptor affinities, while less active compounds possessed lower affinities.