摘要

A group of spirocyclic tropanyl-Delta(2)-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrite 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 %26gt;%26gt; 10 mu M), while some had an IC50 value in the range 5-10 mu M (8a-c, 10b and 11c on DAT, 12b on SERT). Unexpectedly, one of the tertiary amines under investigation, that is 3%26apos;-methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5%26apos;(4%26apos;H)-isoxazole 7a, was able to enhance at a concentration of 10 mu M both [H-3]citalopram and [H-3]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of B-max) and [H-3]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.

  • 出版日期2012-11-1