| 19854053 |
Gray DL, Xu W, Campbell BM, Dounay AB, Barta N, Boroski S, Denny L, Evans L, Stratman N, Probert A: Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6604-7. Epub 2009 Oct 12.
Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1 (A) 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-HT (1A) 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-HT1 (A) 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-HT (1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented. |
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