Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia.
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.
Arena Pharmaceuticals, Inc., San Diego, California, USA. halshamma@arenapharm.com
Hussien A
HA
Al-Shamma
Christen
C
Anderson
Emil
E
Chuang
Remy
R
Luthringer
Andrew J
AJ
Grottick
Erin
E
Hauser
Michael
M
Morgan
William
W
Shanahan
Bradley R
BR
Teegarden
William J
WJ
Thomsen
Dominic
D
Behan
D000293:Adolescent; D000328:Adult; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017286:Polysomnography; D011485:Protein Binding; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis; D011994:Recombinant Proteins; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D055815:Young Adult
D008024:Ligands; D010671:Phenylurea Compounds; D011720:Pyrazoles; D044402:Receptor, Serotonin, 5-HT2A; D011994:Recombinant Proteins; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; C546600:nelotanserin