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Sleep Initiation and Maintenance Disorders: HELP
Articles by Hussien A. Al-Shamma
Based on 5 articles published since 2008
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Between 2008 and 2019, Hussien Al-Shamma wrote the following 5 articles about Sleep Initiation and Maintenance Disorders.
 
+ Citations + Abstracts
1 Clinical Trial Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia. 2010

Al-Shamma, Hussien A / Anderson, Christen / Chuang, Emil / Luthringer, Remy / Grottick, Andrew J / Hauser, Erin / Morgan, Michael / Shanahan, William / Teegarden, Bradley R / Thomsen, William J / Behan, Dominic. ·Arena Pharmaceuticals, Inc., San Diego, California, USA. halshamma@arenapharm.com ·J Pharmacol Exp Ther · Pubmed #19841476.

ABSTRACT: 5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

2 Article Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia. 2012

Xiong, Yifeng / Ullman, Brett / Choi, Jin-Sun Karoline / Cherrier, Martin / Strah-Pleynet, Sonja / Decaire, Marc / Feichtinger, Konrad / Frazer, John M / Yoon, Woo H / Whelan, Kevin / Sanabria, Erin K / Grottick, Andrew J / Al-Shamma, Hussien / Semple, Graeme. ·Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yxiong@arenapharm.com ·Bioorg Med Chem Lett · Pubmed #22325948.

ABSTRACT: A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.

3 Article Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia. 2010

Xiong, Yifeng / Ullman, Brett / Choi, Jin-Sun Karoline / Cherrier, Martin / Strah-Pleynet, Sonja / Decaire, Marc / Dosa, Peter I / Feichtinger, Konrad / Teegarden, Bradley R / Frazer, John M / Yoon, Woo H / Shan, Yun / Whelan, Kevin / Hauser, Erin K / Grottick, Andrew J / Semple, Graeme / Al-Shamma, Hussien. ·Arena Pharmaceuticals, San Diego, California 92121, USA. yxiong@arenapharm.com ·J Med Chem · Pubmed #20684606.

ABSTRACT: Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) 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-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) 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 (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.

4 Article Discovery of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (nelotanserin) and related 5-hydroxytryptamine2A inverse agonists for the treatment of insomnia. 2010

Teegarden, Bradley R / Li, Hongmei / Jayakumar, Honnappa / Strah-Pleynet, Sonja / Dosa, Peter I / Selaya, Susan D / Kato, Naomi / Elwell, Katie H / Davidson, Jarrod / Cheng, Karen / Saldana, Hazel / Frazer, John M / Whelan, Kevin / Foster, Jonathan / Espitia, Stephan / Webb, Robert R / Beeley, Nigel R A / Thomsen, William / Morairty, Stephen R / Kilduff, Thomas S / Al-Shamma, Hussien A. ·Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bradteegarden@ymail.com ·J Med Chem · Pubmed #20143782.

ABSTRACT: Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.

5 Article 5-HT(2A) inverse-agonists for the treatment of insomnia. 2008

Teegarden, Bradley R / Al Shamma, Hussien / Xiong, Yifeng. ·Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. bteegarden@arenapharm.com ·Curr Top Med Chem · Pubmed #18673166.

ABSTRACT: Nearly one half of the adult population in the U.S. experience some symptoms of insomnia (difficulties with getting to sleep, maintaining sleep, and/or sleep quality) on a weekly basis. Although most people with insomnia complain primarily of issues related to sleep maintenance and quality, current therapeutic approaches, including GABA(A) agonists, off label antidepressant use, H(1) antagonists and melatonin agonists, primarily address sleep onset latency. The overall sleep architecture, especially that of the deeper stages of NREM sleep known as slow wave sleep (SWS), plays a crucial role in restorative, restful sleep. Through the 5-HT(2A) receptor, serotonin plays an active role in the regulation of sleep architecture. Antagonists / inverse-agonists of 5-HT(2A), such as APD125, volinanserin, eplivanserin, pruvanserin and pimavanserin, are currently being investigated as therapeutics that could improve the treatment of sleep maintenance and quality in people with insomnia.