Melatonin receptor agonist

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. 

Melatonin receptor agonists in the treatment of sleep disorders... 

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. 

Ramelteon is a melatonin receptor agonist selective for the MTj and MT2 receptors. The dose is 8 mg at bedtime. It is well tolerated, but side effects include headache, dizziness, and somnolence. It is not a controlled substance. 

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]. 

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. 

Pharmacology Ramelteon is a melatonin receptor agonist with high affinity for melatonin MT- and MT2receptors and selectivity over the MTsreceptor. 

Ramelteon is a hypnotic with melatonin receptor agonist activity targeting melatonin MTj and MT2 receptors. It has not been proven to induce dependence. As with zolpidem and zaleplon, no known anxiolytic properties have been elicited. No appreciable activity on serotonin, dopamine, GABA, or acetylcholine is present with the parent compound, but in vitro studies report that its primary metabolite M-II has weak 5-HT2g receptor agonist activity. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Ramelteon is a melatonin receptor agonist selective for the MTj and MT2 receptors. The dose is 8 mg at bedtime. It is well tolerated, but side effects include headache, dizziness, and somnolence. It is not a controlled substance. Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acid (GABA )-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has htde effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Figure 5.11 Afliaity and intrinsic activity profile for the six potential selective MT, melatonin receptor agonists - virtual screening hit compounds a) MT, vj. MT2 affinity and b) MT, Vi. MT2 intrinsic activity.

S20098 is a naphthalenylacetamide derivative, a melatonin analogue and melatonin receptor agonist (acting at Mel,a and Melig subtypes). It is a chronobiotic that potentially may be useful for circadian rhythm disorders. S40015 zolimidine. 

Ramelteon is a melatonin receptor agonist with high afhnity for melatonin MT, and MT2 receptors and selectivity over the MTj receptor. Activation of MTj and MT2 receptors is believed to contribute to ramelteon s sleep-promoting properties. It is indicated in the treatment of insomnia characterized by sleep onset difficulty. 

FIGURE 16.22 (A) Melatonin receptor agonist 93. Enantioselective enzymatic hydrolysis... 

The most recent addition to the armamentarium is the melatonin receptor agonist ramelteon. Molecular modifications to melatonin resulted in this potent and selective melatonin receptor agonist. This medication is very unique in that it does not appear to posses any abuse liability and is not a controlled substance like... 

Melatonin receptor agonists Antihistamines Antidepressants Herbal preparations... 

Osamu Uchikawa 0, Fukatsu K, Tokunoh R, et al., Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002 45 4222-4239. 

Nguyen NN, Yu SS, Song JC. Ramelton a novel melatonin receptor agonist for the treatment of insomnia. Formulary 2005 40 146-155. 

Fig. 4. (A) Synthesis of chiral intermediates for melatonin receptor agonist Enantioselective microbial hydrolysis of racemic epoxide US) to the corresponding (/ )-diol (14) and unreacted (5)-epoxide (12). (B) Stereoinversion of racemic diol (16) to 5-diol (15) by Candida boidinii and Pichia methanolica.

When rat pineal glands were incubated in culture, time-dependent release of arachidonic acid was significantly inhibited by a known 85-kDa cytosolic phospholipase A2 inhibitor, methyl arachi-donyl fiuorophosphonate (Li et al. 2000). Co-incubation with melatonin inhibited the arachidonic acid release in a concentration dependent marmer, and this decrease was accompanied by a reduction of cytosolic phospholipase Aj protein and mRNA expression. Melatonin-receptor agonists, 2-iodo-N-butanoyl-5-methoxytryptamine and 5-methoxycarbonylamino-N-acetyltryptamine,... 

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