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

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

Volume: 3 Issue: 1

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

Affiliation:

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

Abstract: 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.

Cite this article as:

Lattmann Eric, Merino Isidro, Dunn Simon, Parveen Bushra, Lattmann Pornthip, Billington C. David, Bunprakob Yodchai and Sattayasai Jintana, Novel 5-HT7 Ligands as Antidepressants: Automated Synthesis of NSubstituted- N-[1-Methyl-3-(4-Methylpiperidin-1-yl)propyl]-Arylsulfonamides, Letters in Drug Design & Discovery 2006; 3 (1) . https://dx.doi.org/10.2174/157018006775240935