Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT 2A receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 19; pp. 5268 - 5271
• Main Authors: Dewkar, Gajanan K., Peddi, Srinivas, Mosier, Philip D., Roth, Bryan L., Westkaemper, Richard B.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2008
• Subjects: 5-HT 2A; AMDA; Homology model; AMDA; Homology model; 5-HT 2A
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.08.059

The synthesis and 5-HT 2A 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. The effects of methoxy-substitution at the 1-, 2-, 3-, and 4-positions of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on h5-HT 2A 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-HT 2A 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-HT 2A receptor binding sites, whereas the lower-affinity isomers lack this ability.