mdl-100907 and Sleep-Initiation-and-Maintenance-Disorders

Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia").. GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future.. Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.

Topics: Clinical Trials as Topic; Drug Discovery; GABA Modulators; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Intracellular Signaling Peptides and Proteins; Marketing; Neuropeptides; Orexins; Receptors, GABA-A; Receptors, Melatonin; Serotonin 5-HT2 Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome

Benzodiazepine (BZD) and non-BZD hypnotics improve sleep induction and sleep maintenance. BZD induces a further reduction of slow wave sleep (SWS) and rapid eye movement (REM) sleep, whereas SWS and REM values remain decreased during non-BZD administration. There is evidence indicating that the nonselective serotonin 5-HT(2A/2C) receptor antagonists, ritanserin, ketanserin, seganserin and ICI-169369, the selective 5-HT(2A) receptor antagonist eplivanserin and the 5-HT(2A) receptor inverse agonist pimavanserin, increase SWS in subjects with normal sleep. In addition, it has been shown that prior administration of ritanserin prevents the nitrazepam-induced suppression of SWS in normal subjects. Of note, ritanserin also induced an increase of SWS in poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder. The 5-HT(2A) receptor inverse agonist APD-125 gave rise to a similar effect in patients with chronic primary insomnia. Thus, presently available evidence tends to indicate that the association of a 5-HT(2A) receptor antagonist or a 5-HT(2A) receptor inverse agonist with a BZD or a non-BZD hypnotic could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.

Topics: Adult; Animals; Benzodiazepines; Humans; Hypnotics and Sedatives; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep; Sleep Initiation and Maintenance Disorders

In DSM-IV the occurrence of disturbed sleep is one of the principal diagnostic criteria for major depressive disorder (MDD). Further, there is evidence of reciprocity between the two conditions such that, even in the absence of current depressive symptoms, disturbed sleep often predicts their development. The present review discusses the effects of antidepressants on sleep and evaluates the use of the recently developed melatonin agonist-selective serotonin antagonists on sleep and depression. Although many antidepressants such as the tricyclics, monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, several serotonin receptor antagonists and selective serotonin reuptake inhibitors (SSRIs) have all been found successful in treating depression, their use is often associated with a disruptive effect on sleep. SSRIs, currently the most widely prescribed of the antidepressants, are well known for their instigation or exacerbation of insomnia. The recently introduced novel melatonin agonist and selective serotonin antagonist antidepressant, agomelatine, which has melatonin MT(1) and MT(2) receptor agonist and 5-HT(2c) antagonist properties, has been useful in treating patients with MDD. Its rapid onset of action and effectiveness in improving the mood of depressed patients has been attributed to its ability to improve sleep quality. These properties underline the use of melatonin analogues as a promising alternative for the treatment of depression.

Topics: Acetamides; Affect; Antidepressive Agents; Brain; Depressive Disorder, Major; Humans; Indenes; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep; Sleep Initiation and Maintenance Disorders

Topics: Animals; Azabicyclo Compounds; Benzodiazepines; Diphenhydramine; Drug Design; Fluorobenzenes; GABA-A Receptor Agonists; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Indenes; Orexin Receptors; Phenols; Piperazines; Pyridines; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Serotonin 5-HT2 Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Thiophenes; Zolpidem

Lurasidone, an atypical antipsychotic, is a potent 5-HT7 antagonist and D2 , 5-HT2A antagonist, and 5-HT1A partial agonist. As such, lurasidone would be expected to modulate sleep and circadian function but there have been no human studies of the sleep effects of a 5-HT7 antagonist. The purpose of this study was to assess effects of lurasidone on sleep.. This was a cross-over, polysomnographic study involving 54 healthy volunteers who underwent two treatment periods (order randomized) each consisting of two nights in the laboratory: Night 1-lights out at usual bedtime; Night 2-4-h advance of sleep phase and randomization to either lurasidone 40 mg or placebo. The next morning impairment testing was carried out.. Lurasidone significantly (p < 0.05) increased total sleep time by an average of 28.4 min versus placebo, decreased wake time after sleep onset and wake time after the final awakening, and increased sleep efficiency. No other effects were found.. Lurasidone had a sleep maintenance effect without effects on sleep onset, rapid eye movement, or slow-wave sleep. Lurasidone is likely to be beneficial to patients with disturbed sleep, particularly those with sleep maintenance problems. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Adult; Antipsychotic Agents; Cross-Over Studies; Double-Blind Method; Female; Humans; Lurasidone Hydrochloride; Male; Polysomnography; Receptors, Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep Initiation and Maintenance Disorders; Sleep Stages

Topics: Clinical Trials as Topic; Drug Evaluation, Preclinical; Fluorobenzenes; General Practitioners; Humans; Male; Northern Ireland; Piperidines; Scientific Misconduct; Serotonin Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome

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.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Rats; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sleep; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

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.

Topics: Administration, Oral; Amides; Animals; Biological Availability; Blood Proteins; Brain; Dogs; Drug Inverse Agonism; Haplorhini; Humans; Male; Microsomes, Liver; Piperazines; Protein Binding; Pyrazoles; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Sleep; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

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.

Topics: Benzodiazepines; GABA Agonists; Humans; Hypnotics and Sedatives; Serotonin 5-HT2 Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship

Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Ligands; Molecular Structure; Piperidines; Rats; Serotonin 5-HT2 Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship; Time Factors