4.7 Article

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

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 43, Issue 16, Pages 3074-3084

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jm9906062

Keywords

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Funding

  1. NIDA NIH HHS [DA-01642] Funding Source: Medline
  2. NIMH NIH HHS [MH 57019, MH 56650] Funding Source: Medline

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Phenylalkylamines such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; Pa) and its corresponding iodo derivative DOI (2) are commonly used 5-HT2 serotonin agonists. Previous studies have established that the 2,5-dimethoxy substitution pattern found in these compounds is optimal for high affinity at 5-HT2A receptors and that substituents at the 4-position can modulate 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 possesses 5-HT2A antagonist character. The present study examined the structure-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 high affinity. Either of the two methoxy groups can be removed without untoward effect on affinity, and relocation of the methoxy substituents actually enhances affinity by as much as an order of magnitude. None of the compounds 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 relationships of phenylalkylamines as 5-HT2A ligands now be reinvestigated in greater detail.

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