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Synthesis and in Vivo Evaluation of Phenethylpiperazine Amides: Selective 5-Hydroxytryptamine2A Receptor Antagonists for the Treatment of Insomnia

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journal contribution
posted on 12.08.2010, 00:00 by Yifeng Xiong, Brett Ullman, Jin-Sun Karoline Choi, Martin Cherrier, Sonja Strah-Pleynet, Marc Decaire, Peter I. Dosa, Konrad Feichtinger, Bradley R. Teegarden, John M. Frazer, Woo H. Yoon, Yun Shan, Kevin Whelan, Erin K. Hauser, Andrew J. Grottick, Graeme Semple, Hussien Al-Shamma
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT2A receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT2A receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT2A receptor binding affinity, high selectivity over the 5-HT2C receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (δ power) and sleep consolidation at doses as low as 0.1 mg/kg.