Novel 5-HT7 ligands as antidepressants: automated synthesis of N-substituted-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfon amides

Eric Lattmann*, Isidro Merino, Simon Dunn, Bushra Parveen, Pornthip Lattmann, David C. Billington, Yodchal Bunprakob, Jintana Sattayasai

*Corresponding author for this work

Research output: Contribution to journalArticle

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. © 2006 Bentham Science Publishers Ltd.

Original languageEnglish
Pages (from-to)49-54
Number of pages6
JournalLetters in Drug Design and Discovery
Volume3
Issue number1
DOIs
Publication statusPublished - Feb 2006

Keywords

  • 5-HT ligands
  • automated synthesis
  • depression
  • sulfonamides

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