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-HT2A inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT2A receptor with at least 30- and 5000-fold selectivity compared with 5-HT2C and 5-HT2B receptors, respectively. Nelotanserin dosed orally prevented (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT2A 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.
Footnotes
-
This work was supported by Arena Pharmaceuticals Inc., San Diego, CA.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.160994
-
↵
The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- CNS
- central nervous system
- 5-HT
- 5-hydroxytrptamine (serotonin)
- IP
- inositol phosphate
- DOI
- (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
- REM
- rapid eye movement
- NREM
- nonrapid eye movement
- SWS
- slow-wave sleep
- EEG
- electroencephalogram
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- AUC
- area under the plasma exposure curve
- MRT
- mean residency time
- EMG
- electromyogram
- β
- bregma
- AP
- anterioposterior
- ML
- mediolateral
- λ
- lambda
- PSG
- polysomnogram
- MCRT
- Multiple Choice Reaction Time
- CFFT
- Critical Flicker Fusion Test
- RAVLT
- Rey Auditory Verbal Learning Test
- ARCI-49
- Addiction Research Center Inventory
- VAS
- Visual Analog Scale
- DSST
- Digit Symbol Substitution Test
- LSEQ
- Leeds Sleep Evaluation Questionnaire
- GPCR
- G protein-coupled receptor
- CL/F
- clearance from plasma
- Vz/F
- volume of distribution.
- Received August 27, 2009.
- Accepted October 19, 2009.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|