A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake

Clelia Dallanoce, Mara Canovi, Carlo Matera, Tiziana Mennini, Marco De Amici, Marco Gobbi, Carlo De Micheli

Research output: Contribution to journalArticlepeer-review

Abstract

A group of spirocyclic tropanyl-Δ2-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrile oxides to olefins. Their interaction with the dopamine and serotonin transporters (DAT and SERT, respectively) was evaluated through binding experiments. The majority of the compounds had no inhibitory effects (IC50 >> 10 μM), while some had an IC50 value in the range 5-10 μM (8a-c, 10b and 11c on DAT, 12b on SERT). Unexpectedly, one of the tertiary amines under investigation, that is 3′-methoxy-8-methyl-spiro{8-azabicyclo[3.2.1] octane-3,5′(4′H)-isoxazole 7a, was able to enhance at a concentration of 10 μM both [3H]citalopram and [ 3H]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of Bmax) and [3H]serotonin uptake (up to 30%) in cortical synaptosomes. This peculiar pharmacological profile of 7a suggests it binds to an allosteric site on SERT, and positions derivative 7a as a very useful tool to investigate SERT machinery.

Original languageEnglish
Pages (from-to)6344-6355
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number21
DOIs
Publication statusPublished - Nov 1 2012

Keywords

  • Binding affinity
  • Cocaine-related derivatives
  • Cycloaddition reaction
  • Dopamine transporter
  • Serotonin transporter
  • Serotonin uptake potentiation
  • Spirocyclic Δ-isoxazolines

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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