Serotonin receptor affinities of psychoactive phenalkylamine analogues

Employing a rat fundus model, the serotonin (5-HT) receptor affinities of 45 phenalkylamine analogues 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 also enhance receptor affinity, while N,N-dimethylation of the terminal amine decreases affinity. alpha-Methylation of phenethylamines has little effect on affinity when racemates are examined. Introduction of a benzylic keto group can either increase or decrease affinity, depending upon the presence of other aromatic substituents. The most behaviorally active compounds were found to possess the highest 5-HT receptor affinities, while less active compounds were found to possess lower affinities.