138112-76-2 Usage
Uses
Used in Pharmaceutical Industry:
Agomelatine is used as an antidepressant drug for treating major depressive disorder. It works by modulating the activity of melatonin receptors and serotonin receptors, leading to an improvement in mood and a reduction in depressive symptoms.
Used in Neuroprotection Research:
Agomelatine is used as a research compound to study its effects on adult neurogenesis, hippocampus apoptosis, tau protein phosphorylation, and its neuroprotective mechanism. These studies aim to understand the potential therapeutic applications of Agomelatine in various neurological conditions.
Used in Neuroendocrine Model of Depression:
Agomelatine is used as a compound to study its effects on intracellular calcium ([Ca2+]i) signaling in peripheral neurons of rat dorsal root ganglion (DRG) neurons. This helps researchers explore the compound's potential role in modulating neurotransmission and its implications in the treatment of depression.
Chemical Properties:
Agomelatine is a white solid with the following properties:
Acts as an agonist of melatonin (MT) receptors, binding to MT1 and MT2 receptors with Kis of 0.14 and 0.41 nM, respectively.
Acts as an antagonist of serotonin (5-HT) receptor subtypes 5-HT2B and 5-HT2C, with Kis of 0.26 and 0.71 nM, respectively, for the human receptors.
Increases extracellular levels of noradrenaline and dopamine in the frontal cortex of freely moving rats when administered at doses ranging from 20 to 80 mg/kg.
Reduces immobility time in the forced swim test and increases the amount of time spent in the open arms of the elevated plus maze in mice, indicating antidepressant-like and anxiolytic-like activity.
Antidepressants
Agomelatine, which is developed by the French Servier company, is the world's first melatonin receptors MT1 and MT2 agonist class of antidepressants. It applies to the treatment of adult patients with severe depressive. We know that melatonin is an endogenous neural hormones. It is only produced by the pineal gland anterior pituitary at night, and acts on the melatonin receptor that focuses on the presence of hypothalamic suprachiasmatic nucleus (SCN). It is involved in mediating the circadian rhythms in mammals. It is the well-known time guardian in the body, which can regulate the biological clock that is modulated by external circadian cycle. However, since that melatonin has high catabolism rate in vivo which mikes its half-life shorter and the selectivity of its receptor located in the SCN poorer, the treatment of circadian rhythms disorders is limited. Therefore, in order to overcome these drawbacks of melatonin, the researchers designed a series of melatonin analogues. Molecular modeling studies have shown that indole ring of melatonin is the structure sites of catabolic inactivation. Indole ring is an ideal site of isosteric modifications. Agomelatine developed by Servier company is melatonin’s naphthalene biological (electronic) isostere analogs. Indole ring is substituted by naphthalene nucleus, which leads it have more metabolic stability than melatonin.
Pharmacological effects
The listing of agomelatine is a new breakthrough in the field of the treatment of depression. It is melatonin MT1/MT2 receptor agonist and serotonin 2c (5-HT2C) receptor antagonist. It can make depressed patients’ biological rhythm disorders return to normal through the synergy between the two and then result in antidepressant efficacy. Its unique mechanism of action has opened up an innovative way to treat depression. Agomelatine’s mechanism of drug action is completely different with antidepressants that are commonly used today, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). SSRI and SNRI antidepressants achieve antidepressant efficacy by increasing concentration of serotonin. But it also brings a lot of side effects, such as weight changes, sexual dysfunction, withdrawal syndrome and the like. The molecular structure of agomelatine directly combines with serotonin 2c (5HT2c) receptor of post-synaptic membrane so as to exert its antidepressant efficacy without increasing serotonin concentration in the synaptic cleft. This unique mechanism of action makes agomelatine quickly and effectively exert its antidepressant efficacy at the same time, and avoid the occurrence of adverse drug reactions to an extreme.
Another unique targets of agomelatine is in melatonin receptors. MT1 and MT2 receptors densely distribute in the human suprachiasmatic nucleus. The nucleus mainly control human sleep rhythm. Agomelatine can well improve the quality of patients’ sleep by agonism on MT1 MT2 receptors, and improve patients’ wakefulness during the day. The quality of sleep has both cause and effect relationship with depression outcomes state. It is reported that 80% of patients with depression have the problems of sleep disorders at different levels. The improvement of sleep quality can directly contribute to the improvement of the overall clinical condition of patients with depression.
The above information is edited by the lookchem of Ge Qian.
Health risk
October 30, 2012, the British Medicines and Healthcare Products Agency (MHRA) released agomelatine (agomelatine, Valdoxan/Thymanax) security information. MHRA found that several cases appears serious reports of liver toxicity with agomelatine, including six cases of liver failure patients within worldwide report. Agomelatine's drug information already includes in the recommendations that all patients need liver function tests at the start of treatment and during treatment. Now liver function tests should also be recommended when the drug dose is increased. MHRA recommends that if the patients have potential liver damage symptoms or signs, or that the increases of serum transaminase beyond the upper limit of normal (ULN) three times is found in the function tests, it should be immediately suspended.
Patent cases
The earliest agomelatine compound patent is French Patent FR902393, which is applied in February 27, 1990. This patent has the same patent family in Europe, USA, Canada, Japan and Australia. But there is no Chinese patent. The above patents were all authorized after January 1, 1993. Therefore China is also ineligible for administrative protection. Agomelatine has both technology patent and polymorph patent in China. But it also can be avoided.
Biochem/physiol Actions
Agomelatine is an extremely potent agonist at both melatonin receptors (MT1 and MT2), with additional antagonism at 5HT2C. It is a novel antidepressant with many desired in vivo properties, including neuroprotection and neurogenesis in depression-sensitive brain areas. Agomelatine′s efficacy appears to be due to both melatonergic and serotonergic properties. In neurogenesis assays, both in vitro and in vivo, the compound effects were differentially affected by antagonists for MT1/MT2 and 5HT2C, demonstrating actions through all three receptors.
Clinical Use
Antidepressant
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: avoid with ciprofloxacin.
Antidepressants: metabolism inhibited by
fluvoxamine.
Antimalarials: avoid with artemether with
lumefantrine and artenimol with piperaquine.
Metabolism
Agomelatine is rapidly metabolised, mainly by the hepatic
cytochrome P450 isoenzyme CYP1A2; the isoenzymes
CYP2C9 and CYP2C19 also make a minor contribution.
The major metabolites, hydroxylated and demethylated
agomelatine, are not active and are rapidly conjugated and
eliminated in the urine.
references
[1] zupancic m, guilleminault c. agomelatine. cns drugs, 2006, 20(12): 981-992.
Check Digit Verification of cas no
The CAS Registry Mumber 138112-76-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,8,1,1 and 2 respectively; the second part has 2 digits, 7 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 138112-76:
(8*1)+(7*3)+(6*8)+(5*1)+(4*1)+(3*2)+(2*7)+(1*6)=112
112 % 10 = 2
So 138112-76-2 is a valid CAS Registry Number.
InChI:InChI=1/C11H14N4O2.CH4O3S/c1-5-2-9(16)7-3-8(14-15-11(12)13)10(17)4-6(5)7;1-5(2,3)4/h3-5,9,16H,2H2,1H3,(H4,12,13,15);1H3,(H,2,3,4)/b14-8-;
138112-76-2Relevant articles and documents
Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An Antidepressant Drug
Vujjini, Satish Kumar,Vyala, Sunitha,Badarla, Krishna Rao,Kandala, Sreenatha Charyulu,Bandichhor, Rakeshwar,Kagga, Mukkanti,Cherukupalli, Praveen
, p. 1864 - 1870 (2015)
A simple and efficient process for the large-scale preparation of agomelatine (1), an antidepressant drug is, described. Agomelatine was prepared in a linear manner starting from readily available, inexpensive 2-naphthol. Key steps in the synthesis are Friedel-Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of keto intermediate, and nucleophilic displacement of chloro intermediate with sodium diformylamide. A systemic approach was described to streamline the process into a robust scalable process by controlling the impurities.
A facile synthesis of melatonergic antidepressant agomelatine
Kandagatla, Bhaskar,Raju, Vetukuri Venkata Naga Kali Vara Prasada,Reddy, Ganta Madhusudhan,Rao, Sirigiri Chandrakanth,Iqbal, Javed,Bandichhor, Rakeshwar,Oruganti, Srinivas
, p. 7125 - 7127 (2012)
Agomelatine was synthesized from 8-aminonaphthalen-2-ol by diazotization-iodination, formylation, C-C bond formation by nitroaldol and Pd/C hydrogenation of β-nitrovinylnaphthalene followed by N-acetylation. The route reported employs readily and commercially viable starting materials and reagents, and can potentially be utilized for process synthesis of agomelatine.
A simple and efficient procedure for synthesis of agomelatine
Gurunadham,Raju, R. Madhusudhan,Venkateswarlu
, p. 1367 - 1370 (2016)
A simple and efficient process for the large scale preparation of agomelatine, an antidepressant drug is described. Agomelatine was synthesized from 7-methoxy-1-tetralone in five steps. The route reported employs readily, commercially viable starting materials, reagents and potentially be utilized for the process of synthesis of agomelatine.
Novel conformationally constrained analogues of agomelatine as new melatoninergic ligands
Rami, Marouan,Landagaray, Elodie,Ettaoussi, Mohamed,Boukhalfa, Koussayla,Caignard, Daniel-Henri,Delagrange, Philippe,Berthelot, Pascal,Yous, Said
, p. 154 - 166 (2013)
Novel conformationally restricted analogues of agomelatine were synthesized and pharmacologically evaluated at MT1 and MT2 melatoninergic receptors. Replacement of the N-Acetyl side chain of agomelatine by oxathiadiazole-2-oxide (compound 3), oxadiazole-5(4H)-one (compound 4), tetrazole (compound 5), oxazolidinone (compound 7a), pyrrolidinone (compound 7b), imidazolidinedione (compound 12), thiazole (compounds 13 and 14) and isoxazole moieties (compound 15) led to a decrease of the melatoninergic binding affinities, particularly at MT1. Compounds 7a and 7b exhibiting nanomolar affinity towards the MT2 receptors subtypes have shown the most interesting pharmacological results of this series with the appearance of a weak MT2-selectivity.
A novel synthesis of the antidepressant agomelatine
Markl, Christian,Zlotos, Darius P.
, p. 79 - 82 (2011)
Agomelatine was synthesized from (2-methoxynaphthalene-8-yl)oxoacetic acid in a four-step approach involving borane reduction, semipinacol rearrangement of the resulting diol, ald-oxime formation, and Ra-Ni hydrogenation/acetylation in 51% overall yield. The reaction sequence includes a novel one-pot conversion of an aldoxime into an N-acetylamine. The synthetic route could be useful as a new approach towards N-acetylarylethyl-amines. Georg Thieme Verlag Stuttgart · New York.
Total synthesis of agomelatine via Friedel-Crafts acylation followed by Willgerodt-Kindler reaction
Vujjini, Satish Kumar,Datla, V.R. Krishnam Raju,Badarla, Krishna Rao,Vetukuri, V.N.K.V. Prasada Raju,Bandichhor, Rakeshwar,Kagga, Mukkanti,Cherukupally, Praveen
, p. 3885 - 3887 (2014)
Total synthesis of antidepressant drug, agomelatine is reported. Regio selective Friedel-Crafts acylation followed by Willgerodt-Kindler reactions is used as the key steps for the synthesis of agomelatine.
Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands
Depreux,Lesieur,Mansour,Morgan,Howell,Renard,Caignard,Pfeiffer,Delagrange,Guardiola,Yous,Demarque,Adam,Andrieux
, p. 3231 - 3239 (1994)
A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2- 125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.
PROCESS FOR THE PREPARATION OF AGOMELATINE IN CRYSTALLINE FORM
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Page/Page column 41, (2019/05/02)
The present invention pertains to a process for the preparation of polymorph form X of agomelatine, which comprises providing agomelatine, and crystallizing agomelatine in the presence of at least one of an acid and a salt thereof, and to a polymorph form of agomelatine.
Preparation method of agomelatine
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, (2018/09/11)
The invention provides a preparation method of agomelatine. According to the preparation method, 7-methoxy-1-naphthaldehyde is taken as a substrate, and three reaction steps including a condensation dehydration reaction, a reduction reaction and a acetylation reaction are respectively carried out. The preparation method disclosed by the invention has the beneficial effects that the process is simple and only comprises three reaction steps, the operation is convenient, and the industrial production is easily realized; secondly, synthetic raw materials are easily available and cheap, and the cost of the whole process is very low; thirdly, the agomelatine product prepared by virtue of the preparation method reaches up to 99.9%, and the quality of the agomelatine product meets the requirementsof European and the United States Pharmacopoeias; and finally, the agomelatine product prepared by virtue of the preparation method is high in yield, and the total yield reaches 64%.
Preparation method of agomelatine
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Paragraph 0018; 0022; 0026, (2018/01/12)
The invention discloses a preparation method of agomelatine. In the method, 1-methyl-7-methoxynaphthalene is used as an initial raw material and is successively subjected to a bromination reaction with N-bromosuccinimide, a substitution reaction with nitromethane, a nitro-reduction reaction, and an acetylation reaction to produce a final product of agomelatine. The preparation method has fewer steps and employs low-cost and easy-to-obtained raw materials. During the reactions, high-risk and high-cost hydrogenation catalysts, such as palladium-carbon and Raney nickel, are not employed, so that the reactions are more reliable and require lower energy. The method can reduce transfer loss of intermediates, is simpler in operation, occupies fewer operators, is stable in product quality and high in yield and is suitable for large-scale industrial stable production.
