Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
Email: lddd@benthamscience.org


Novel 5-HT7 Ligands as Antidepressants: Automated Synthesis of NSubstituted- N-[1-Methyl-3-(4-Methylpiperidin-1-yl)propyl]-Arylsulfonamides

Author(s): Eric Lattmann, Isidro Merino, Simon Dunn, Bushra Parveen, Pornthip Lattmann, David C. Billington, Yodchai Bunprakob, Jintana Sattayasai.


The 5-HT7 receptor is linked with various CNS disorders. Using an automated solution phase synthesis a combinatorial library of 384 N-substituted N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]- arylsulfonamides was prepared with 24 chemically diverse amines 1-24 and 16 sulfonyl chlorides A-P. The chemical library of alkylated sulfonamides was evaluated in a receptor binding assay with [3]H-5-CT as ligand. The key synthetic step was the alkylation of a sulfonamide with iodide E, which was prepared from butanediol in 4 synthetic steps. The target compounds 1A, 1B.....24A ... 24P were purified by solvent extraction on a Teacan liquid handling system. Sulfonamide J20, B23, D23, G23, G23, J23 , I24 and O24 displayed a binding affinity IC50 between 100 nM and 10 nM. The crystalline J20 (IC50=39 nM) and O24 (IC50=83 nM) were evaluated further in the despair swimming test and the tail suspension assay. A significant antidepressant activity was found in mice of a greater magnitude than imipramine and fluoxetine at low doses.

Keywords: 5-HT7 ligands, sulfonamides, automated synthesis, depression

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Article Details

Year: 2006
Page: [49 - 54]
Pages: 6
DOI: 10.2174/157018006775240935