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.

A novel spirocyclic tropanyl-Delta(2)-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake / C. Dallanoce, M. Canovi, C. Matera, T. Mennini, M. De Amici, M. Gobbi, C. De Micheli. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 20:21(2012 Nov 01), pp. 6344-6355.

A novel spirocyclic tropanyl-Delta(2)-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake

C. Dallanoce
;
C. Matera;M. De Amici;C. De Micheli
Ultimo
2012

Abstract

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.
Cocaine-related derivatives; Spirocyclic Delta(2)-isoxazolines; Cycloaddition reaction; Binding affinity; Dopamine transporter; Serotonin transporter; Serotonin uptake potentiation
Settore CHIM/08 - Chimica Farmaceutica
1-nov-2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/215417
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