Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

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 (Ϯ)-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.Serotonin has long been implicated in the regulation of sleep and wakefulness. Central serotonergic neurons of the dorsal raphe nucleus form part of the reticular activating system that innervates cortical and subcortical regions of the forebrain. As its name implies, this system modulates arousal in the central nervous system (CNS) and regulates sleep/wake states (Abrams et al., 2005). Within this system, 5-HT neurons are active during wakefulness, less active during nonrapid eye movement (NREM) sleep, and inactive during rapid eye movement (REM) sleep.5-HT activity in the CNS is mediated by multiple receptor subtypes that are classified into seven subfamilies (5-HT 1 to 5-HT 7 ) (Hoyer et al., 1994). The 5-HT 2 subfamily includes three subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C . Unlike 5-HT 2B receptors, which have limited CNS expression, 5-HT 2A and 5-HT 2C receptors are widely distributed in the CNS in areas that are implicated in the regulation of sleep and waking (Leysen, 2004). There is compelling preclinical and clinical evidence that supports a role for 5-HT 2A antagonism in the treatment of sleep maintenance insomnias (Borbély et al., This work was supported by Arena Phar...

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [3H]JNJ-40068782

“…At relatively high concentrations, JNJ-40068782 also acted on the 5HT 2A receptor (IC 50 , ∼10 mM); it is, however, unlikely that it reaches sufficient amounts in vivo to trigger a functional 5HT 2A -related effect. Using [ we did not observe in vivo binding up to 30 mg/kg PO (data not shown); also in addition, JNJ-40068782 did not affect sleepwake behavior in rats, whereas ample evidence exists for modulation of deep non-REM sleep via the 5HT 2A receptor (Al-Shamma et al, 2010 3 H]DCG-IV is interesting and may suggest that PAMs preferentially bind to certain receptor states that are not necessarily similar to those preferentially recognized by DCG-IV. Alternatively, JNJ-40068782 may bind to only one of the subunits within the mGlu2 homodimer, whereas DCG-IV likely binds to both, which might be consistent with previous reports that binding and closure of both extracellular domains within the mGlu receptor dimer are needed for full activity, whereas only a single heptahelical domain is turned on upon receptor activation (Kniazeff et al, 2004;Hlavackova et al, 2005).…”

Differential Effects of Sodium Oxybate and Baclofen on EEG, Sleep, Neurobehavioral Performance, and Memory

“…For instance, the serotonergic system seems to be also involved in the generation of EEG slow waves. 67,68 Interestingly, both BAC and GHB affect the serotonergic system, apparently through GABA B receptors. 69,70 Several physiological and behavioral processes, including cognition, anesthesia, coma, and sleep, are closely linked with slow wave generation/synchronization.…”

Role of 5-HT2A receptor antagonists in the treatment of insomnia

“…The increase in slow-wave sleep caused by 5-HT 2 antagonists in rats appears to be more predictive of effects in humans than are the cat data (see below). Other 5-HT 2 receptor antagonists, such as Fananserin, pruvanserin, and nelotanserin, have shown increases in non-REM or slow-wave sleep in rats,29,39,40 and eplivanserin and pruvanserin also show decreases in REM sleep in rats 29,31. The data with nelotanserin further suggest that 5-HT 2A receptor antagonism or inverse agonism is associated with increased sleep consolidation, as evidenced by a statistically significant increase in non-REM bout duration and a statistically significant decrease in the number of non-REM bouts in rats 39.…”