A1748-5mg | Ramelteon [196597-26-9] Clinisciences

Background

Ramelteon, a chronohypnotic, is an orally active and highly selective melatonin receptor (MT1, MT2 and MT3) agonist that preferentially binds to MT1 and MT2 receptors leading to potent inhibition of cAMP production in human cells expressing MT1 or MT2 receptors with the half maximal inhibition concentration IC50 values of 21.2 pM/L and 53.4 pM/L respectively [1].

The s-configuration and ether group in the chemical structure of ramelteon confer its high affinity towards MT1 and MT2 receptors with the dissociation constant Ki values of 14 pM and 112 pM respectively in comparison with that of 2650 nM for MT3 receptors [1].

Ramelteon has been found to potently promote sleep without causing any significant adverse effects leading to its application for the treatment of insomnia [1].

References:
[1] Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. doi: 10.1111/j.1755-5949.2008.00066.x.

Product Citation

1. Cassar S, Beekhuijzen M, et al. "A multi-institutional study benchmarking the zebrafish developmental assay for prediction of embryotoxic plasma concentrations from rat embryo-fetal development studies." Reprod Toxicol. 2019 Jun;86:33-44. PMID:30876927

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	259.34
Cas No.	196597-26-9
Formula	C₁₆H₂₁NO₂
Solubility	insoluble in H2O; ≥12.95 mg/mL in DMSO; ≥54.9 mg/mL in EtOH
Chemical Name	N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzofuran-8-yl]ethyl]propanamide
SDF	Download SDF
Canonical SMILES	CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
Binding assays	Cells stably expressing MT1 or MT2 receptors (CHO-hMelR7) were selected and cultured in Eagle’s Minimum Essential Medium-α (MEM-α) supplemented with 10% dialyzed fetal bovine serum (dFBS) under a 5% CO2/95% air atmosphere. Cells were harvested at confluence in Ca2+-Mg2+ free Hanks’ balanced salt solution containing 5 mM EDTA and collected by centrifugation. Cells were homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7 at 25℃), washed twice, pelleted, and stored at -30℃ until the binding assays were conducted. Ramelteon and 40 pM 2-[125I]melatonin were mixed with the thawed homogenate in a total volume of 1 mL and incubated at 25℃ for 150 min. The reaction was terminated by addition of 3 mL of icecold buffer followed by vacuum filtration on a Whatman GF/B. The filter was washed twice and radioactivity was counted by a γ-counter. Nonspecific binding was defined as the binding in the presence of 10 mM melatonin.
Cell experiment [2]:
Cell lines	Pancreatic INS-1 β-cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reaction Conditions	2-14 h
Applications	Ramelteon is a potent and selective agonist of MT1/MT2 melatonin receptors. Ramelteon inhibits forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors [2]. Ramelteon is capable of increasing brain-derived neurotrophic factor (BDNF) protein in neurons expressing either MT1 or MT2 receptor type in mouse cerebellar granule cells [3].
Animal experiment [4]:
Animal models	Freely moving cats
Dosage form	0.001, 0.01, and 0.1 mg/kg; administered orally.
Preparation method	Suspended in a 0.5% (weight per volume) methylcellulose solution.
Applications	In cats, ramelteon has a sleep-promoting action and does not appear to cause learning, memory, or motor function impairment, or to have rewarding properties [4]. In a clinical study, ramelteon decreases latency to persistent sleep and increases total sleep time and sleep efficiency in subjects with primary chronic insomnia [1].
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology, 2005, 48(2): 301-310. [2]. Nishiyama K, Hirai K. The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 β-cells. PLoS One, 2014, 9(7): e102073. [3]. Imbesi M, Uz T, Dzitoyeva S, et al. Stimulatory effects of a melatonin receptor agonist, ramelteon, on BDNF in mouse cerebellar granule cells. Neurosci Lett, 2008, 439(1): 34-36. [4]. Miyamoto M, Nishikawa H, Doken Y, et al. The sleep-promoting action of ramelteon (TAK-375) in freely moving cats. Sleep, 2004, 27(7): 1319-1325.

Biological Activity

Description	Ramelteon is a selective agonist of MT1/MT2 with Ki values of 0.014 nM and 0.045 nM, respectively.
Targets	MT1	MT2
IC50	0.014 nM (Ki)	0.045 nM (Ki)

Quality Control

Purity = 99.89%

Chemical structure

Ramelteon [196597-26-9]

Referentie A1748-5mg

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