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

Authors:
Clelia Dallanoce
Clelia Dallanoce
Università degli Studi di Milano
Italy
Mara Canovi
Mara Canovi
Università degli Studi di Milano
Italy
Carlo Matera
Carlo Matera
Università degli Studi di Milano
Tiziana Mennini
Tiziana Mennini
Mario Negri Institute for Pharmacological Research
Italy
Prof Marco Gobbi, Md
Prof Marco Gobbi, Md
Università di Genova
Professor
Hematology
Genova, Liguria | Italy

Bioorg Med Chem 2012 Nov 10;20(21):6344-55. Epub 2012 Sep 10.

Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.

A group of spirocyclic tropanyl-Δ(2)-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 (IC(50) > 10 μM), while some had an IC(50) 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 [(3)H]citalopram and [(3)H]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of B(max)) and [(3)H]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.

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http://dx.doi.org/10.1016/j.bmc.2012.09.004DOI Listing

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November 2012
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