Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT2A receptor

https://doi.org/10.1016/j.bmcl.2008.08.059Get rights and content

Abstract

The effects of methoxy-substitution at the 1-, 2-, 3-, and 4-positions of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on h5-HT2A receptor affinity were determined. Racemic mixtures of these compounds were found to show the following affinity trend: 3-MeO > 4-MeO > 1-MeO  2-MeO. Comparison of the effects of these substitutions, with the aid of computational molecular modeling techniques, suggest that the various positional and stereochemical isomers of the methoxy-substituted AMDA compounds interact differently with the h5-HT2A receptor. It is predicted that for the compounds with higher affinities, the methoxy oxygen atom is able to interact with hydrogen bond-donating sidechains within alternative h5-HT2A receptor binding sites, whereas the lower-affinity isomers lack this ability.

Graphical abstract

The synthesis and 5-HT2A receptor affinities of a series of methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives are reported. Molecular modeling techniques are used to elucidate probable binding modes for the compounds.

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Acknowledgments

This work was supported by United States Public Health Service Grant R01-MH57969 (RBW), R01-MH57635 (BLR), K02-MH01366 (BLR) and R01-MH61887 (BLR), U19-MH82441 (BLR) and the NIMH Psychoactive Drug Screening Program (BLR).

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