Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist

Kato, Kanefusa; Hirai, Keisuke; Nishiyama, Keiji; Uchikawa, Osamu; Fukatsu, K.; Ohkawa, Shigenori; Kawamata, Yuji; Hinuma, Shuji; Miyamoto, Masaomi

doi:10.1016/j.neuropharm.2004.09.007

Cited by 498 publications

(250 citation statements)

References 40 publications

Supporting

Mentioning

241

Contrasting

Unclassified

Order By: Relevance

“…4B). These doses are well within the range for specific melatonin receptor activation (31). By contrast, neither melatonin nor ramelteon affected the circadian period of SCN explants from wild-type mice.…”

Section: Wild Typementioning

confidence: 60%

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Shimomura¹,

Lowrey

Vitaterna³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Most laboratory mouse strains including C57BL/6J do not produce detectable levels of pineal melatonin owing to deficits in enzymatic activity of arylalkylamine N-acetyltransferase (AANAT) and Nacetylserotonin O-methyl transferase (ASMT), two enzymes necessary for melatonin biosynthesis. Here we report that alleles segregating at these two loci in C3H/HeJ mice, an inbred strain producing melatonin, suppress the circadian period-lengthening effect of the Clock mutation. Through a functional mapping approach, we localize mouse Asmt to chromosome X and show that it, and the Aanat locus on chromosome 11, are significantly associated with pineal melatonin levels. Treatment of suprachiasmatic nucleus (SCN) explant cultures from Period2 Luciferase (Per2 Luc ) Clock/+ reporter mice with melatonin, or the melatonin agonist, ramelteon, phenocopies the genetic suppression of the Clock mutant phenotype observed in living animals. These results demonstrate that melatonin suppresses the Clock/+ mutant phenotype and interacts with Clock to affect the mammalian circadian system.C ircadian (from the Latin, meaning about a day) rhythms of biochemistry and physiology are innate to virtually all life forms (1, 2). Cell autonomous circadian pacemakers drive these rhythms and synchronize them each day to environmental cues. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains the central pacemaker that coordinates the local circadian clocks present in tissues throughout the body (3, 4). The molecular clock mechanism within individual cells is composed of transcriptional/translational feedback loops and posttranslational processes (1, 5). The bHLH-PAS transcription factors CLOCK and BMAL1 form the primary loop as they activate transcription of the Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2) genes (1, 6). The PER and CRY proteins subsequently feed back to abrogate their own transcription by directly inhibiting the CLOCK:BMAL1 complex. A second feedback loop stabilizes the primary loop and is composed of REV-ERBα and RORa, two retinoic acid-related orphan receptors, which repress and activate, respectively, transcription of Bmal1. Whereas approximately a dozen genes involved in this timekeeping system have been identified in mammals, it is clear that other, as-yet unknown genes regulate key properties of circadian rhythms (7,8).The SCN imparts daily entraining signals to circadian clocks in cells of peripheral tissues via neural connections and humoral factors (9, 10). One well-characterized circadian rhythm synchronized by the SCN is the synthesis and release at night of the lipophilic pineal hormone melatonin (11). Light information reaches the mammalian pineal gland through a multisynaptic pathway that begins with intrinsically photosensitive melanopsin-containing retinal ganglion cells, which project to the SCN via the retinohypothalamic tract, and ultimately terminates at sympathetic afferents of the pineal gland (12, 13). Lesions of the SCN abolish the melatonin circadian rhythm (14). Two high-affi...

show abstract

Section: Wild Typementioning

confidence: 60%

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Shimomura¹,

Lowrey

Vitaterna³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Ramelteon, a melatonin receptor agonist, has a high affinity for the melatonin receptors (44). Previous case reports indicated that the administration of melatonin ago-…”

Section: Melatonin Agonist Ramelteon In Deliriummentioning

confidence: 99%

Are Melatonin and its Agonist the Natural Solution for Prevention of Delirium in Critically Ill Patients? A Review of Current Studies

Aghakouchakzadeh

Izadpanah

Soltani

et al. 2017

Jundishapur J Nat Pharm Prod

View full text Add to dashboard Cite

Background: Delirium is a neuropsychiatric syndrome, which is a common complication at the intensive care unit (ICU). Delirium is a risk factor for increased duration of mechanical ventilation and increased time of stay at the ICU and death. Melatonin is a hormone produced and secreted by the pineal gland, that regulates circadian rhythm. The aim of this investigation was to demonstrate the effect of melatonin in controlling and improving delirium.

show abstract

“…The MT1 receptor is thought to attenuate the alerting signal of the SCN and thereby the occupation of the MT1 receptor decreases sleep latency. The MT2 receptor is thought to have phase-shifting properties, meaning it has the potential to alter the timing of sleep and wake [58]. Remelteon, the 1 approved melatonin agonist, has a rapid onset of effect having a Tmax of 0.75 h, and it has an ultra-short half-life of 1-2.6 h (see Table 1).…”

Section: Pharmacologymentioning

confidence: 99%

Insomnia Pharmacotherapy

2012

View full text Add to dashboard Cite

Summary The benzodiazepine receptor agonists (BzRAs) a melatonin receptor agonist and a histamine antagonist have all been approved as hypnotics. Beyond their differing mechanisms of action, they have differences in pharmacokinetics, and among the BzRAs differences in receptor subtype affinity and formulations, which provides the physician with broad options for tailoring therapy to each patient's specific needs. Consistent with their specific pharmacokinetics and formulations, these Food and Drug Administration-approved hypnotics have been shown to improve sleep with no evidence of tolerance development in long-term use. In addition, emerging data indicate these drugs also improve aspects of daytime function. Their side effects are either associated with the direct sedating effects of the drugs, doses greater than clinical doses, or a combination with alcohol or other sedating drugs. Anxiolytic BzRAs, sedating antidepressants and antipsychotics have been used off-label as hypnotics. However, in the absence of information regarding their dose range for efficacy and safety, their use as hypnotics is ill-advised.

show abstract

Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist

Cited by 498 publications

References 40 publications

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Are Melatonin and its Agonist the Natural Solution for Prevention of Delirium in Critically Ill Patients? A Review of Current Studies

Insomnia Pharmacotherapy

Contact Info

Product

Resources

About