1-[4-(3-phenylalkyl)phenyl]-2-aminopropanes as 5-HT2A partial agonists

Phenylalkylamines such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (D OB; Pa) and its corresponding iodo derivative DOI (2) are commonly used 5-H T2 serotonin agonists. Previous studies have established that the 2,5-dimet hoxy substitution pattern found in these compounds is optimal for high affi nity at 5-HT2A receptors and that substituents at the 4-position can modula te affinity over a wide range. We have previously shown, however, that when the 4-position is substituted with a 3-phenylpropyl substituent (i.e., 3), the compound binds with an affinity comparable to that of Pa but that it p ossesses 5-HT2A antagonist character. The present study examined the struct ure-affinity relationships of 3, and the results were very much unexpected. That is, the 2,5-dimethoxy substitution pattern of 3 is not required for h igh affinity. Either of the two methoxy groups can be removed without untow ard effect on affinity, and relocation of the methoxy substituents actually enhances affinity by as much as an order of magnitude. None of the compoun ds displayed more than 20-fold selectivity for 5-HT2A over 5-HT2C receptors . In addition, several were demonstrated to act as 5-HT2A partial agonists. As such, the results of this study suggest that the structure-affinity rel ationships of phenylalkylamines as 5-HT2A ligands now be reinvestigated in greater detail.