Design, synthesis, and structure-activity relationship studies of a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines: Insights into structural features contributing to dopamine D3 versus D2 receptor subtype selectivity

Subramaniam Ananthan, Surendra K. Saini, Guangyan Zhou, Judith V. Hobrath, Indira Padmalayam, Ling Zhai, J. Robert Bostwick, Tamara Antonio, Maarten E.A. Reith, Shea McDowell, Eunie Cho, Leah McAleer, Michelle Taylor, Robert R. Luedtke

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29 Scopus citations

Abstract

Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands.

Original languageEnglish
Pages (from-to)7042-7060
Number of pages19
JournalJournal of Medicinal Chemistry
Volume57
Issue number16
DOIs
StatePublished - 28 Aug 2014

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    Ananthan, S., Saini, S. K., Zhou, G., Hobrath, J. V., Padmalayam, I., Zhai, L., Bostwick, J. R., Antonio, T., Reith, M. E. A., McDowell, S., Cho, E., McAleer, L., Taylor, M., & Luedtke, R. R. (2014). Design, synthesis, and structure-activity relationship studies of a series of [4-(4-carboxamidobutyl)]-1-arylpiperazines: Insights into structural features contributing to dopamine D3 versus D2 receptor subtype selectivity. Journal of Medicinal Chemistry, 57(16), 7042-7060. https://doi.org/10.1021/jm500801r