Agonists insomnia

Benzodiazepines, ie, the hiU BZR agonists, are prescribed for anxiety, insomnia, sedation, myorelaxation, and as anticonvulsants (97). Those benzodiazepines most commonly prescribed for the treatment of anxiety disorders are lorazepam (19), alprazolam (20), diazepam (21), bromazepam (22), chlorazepate (23), and oxazepam (24). These dmgs together represent about 70% of total... 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

The two selective GABA j receptor agonists currently marketed in the United States, zaleplon and Zolpidem, are a pyrazolopyrimidine and a imidaz-opyridine, respectively. Both of these drugs are approved only for the shortterm treatment of insomnia. 

BP 2.94) or (5) (Sch 50971) induce significant increases of slow-wave sleep or induce sedation in animal models [10, 33]. Potent and selective brain-penetrating H3 agonists could provide a new therapeutic option for the treatment of insomnia. 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

LY 156735 is a [1-substituted analog of melatonin that has greater bioavailability than melatonin (Nickelsen et al. 2002). It is in an earlier stage of clinical trials in initial trials, it reduced the sleep onset time in patients with moderate sleep-onset insomnia. Several other specific melatonin receptor agonists and antagonists are in development (Rivara et al. 2005 Zlotos 2005) and presumably will be clinically tested over the next few years. 

Gaboxadol (9) is a selective extrasynaptic GABA receptor agonist in late-stage investigation for the treatment of insomnia. The action of this compound was extensively reviewed in Chebib et al. [13] and updated in Wafford et al. [23]. Nevertheless, the sponsor companies Merck Co., Inc., and H. Lundbeck A/S announced in March 2007 that the results from recently completed clinical studies do not support further development and announced the discontinuation of their joint development program for gaboxadol. 

NG2-73 is a GABAa receptor partial agonist that, according to the information given by the company, modulates preferentially the a3 subunit - a subunit that is hypothesized to be associated with sleep induction - and is undergoing phase II trials for chronic insomnia with primary endpoints measuring sleep onset as well as maintenance (no structure disclosed) [25]. 

To mimic melatonin action and increase the half-life is the goal of melatonin receptor agonists, which are the more recent addition to the insomnia therapeutic armamentarium. These compounds, in addition to use for insomnia, may have potential application in the synchronization of disturbed circadian rhythms, sleep disturbances in the elderly, seasonal depression and jet lag, to name a few. Furthermore, studies have shown that melatonin receptor agonists do not induce any of the hypothermic, hypotensive or bradycardic effects caused by melatonin in humans [27,28]. 

Takeda s melatonin (MT1/MT2) receptor agonist ramelteon (11) was approved and launched in 2005 in the U.S., indicated for the treatment of primary insomnia characterized by difficulty with sleep onset. It is the first prescription medication for insomnia with a novel mechanism of action to reach the US market in 35 years. It is also the first and only prescription sleep medication that has not exhibited potential for abuse and dependence, and as such is not designated as a scheduled substance by the DEA. Moreover, ramelteon was also filed in late March 2007 in E.U. for primary insomnia. 

Pimavanserin tartrate (40, ACP-103) is a 5-HT2A receptor inverse agonist currently in phase II clinical development as an antipsychotic agent and for insomnia, focused on sleep maintenance, evaluating slow-wave-sleep at doses of 5 and 20 mg [97,98]. 

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