No abstract

No abstract

No 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.

No 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...

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl-)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to membranes (K i ϭ 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC 50 ϭ 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT 2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT 2A receptor versus 5-HT 2C and 5-HT 2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC 50 ϭ 8.7 and 23.1 nM, respectively).Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC 50 ϭ 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT 2A receptor antagonist with potent activity on platelets and vascular smooth muscle.Serotonin (5-hydroxytryptamine, 5-HT) is a naturally occurring indoleamine found primarily in brain, enterochromaffin tissue, and platelets. 5-HT exerts a multitude of biological effects mediated through interaction with specific cell surface G-protein-coupled receptors (GPCRs). To date, at least 14 different human 5-HT GPCRs are known (Kaumann and Levy, 2006). Among them, 5-HT 2A receptors on vascular smooth muscle cells and platelets play an important role in the regulation of cardiovascular function.The uptake process and storage capacity for 5-HT by platelets are such that minimal amounts of the amine exist in normal plasma. However, upon platelet activation at sites of vessel injury, 5-HT is released from the dense granules in platelets (Ashton et al., 1986). Although 5-HT by itself is only a weak activator of platelet aggregation, it effectively amplifies aggregation induced by other agonists including collagen, ADP, epinephrine, and thrombin (De Clerck and Herman, 1983;De Clerck and Janssen, 1990). Thus, 5-HT This work was supported by Arena Pharmaceuticals, Inc. Article, publication date, and citation information can be found at

The synthesis and preliminary evaluation of 10 and 11, stable precursors to the inherently reactive but isolable p-quinonemethide analog 9 of the CC-1065 and duocarmycin alkylation subunits, are detailed. The p-quinonemethide 9, while reactive {ty% < 1 min, CH3OH), represents one of the few unsubstituted quinonemethides sufficiently stable for isolation and characterization. The structural origin of this stability and the ramifications of the observations on the origin of the stability of the CC-1065 and duocarmycin alkylation subunits are discussed.