Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1A partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT1A receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1A partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT1A in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.

The discovery of piperidine diphenyl ethers (16) which combine norepinephrine reuptake inhibition (NRI) with 5-HT1A partial agonist activity is described. Potent and selective leads were discovered starting from high-throughput screening hits including 1.Figure optionsDownload as PowerPoint slide