褪黑素 | 73-31-4

• 物质功能分类: 原料药 - 影响免疫功能药 - 免疫调节药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 褪黑素
• 中文别名: N-乙酰基-5-甲氧基色胺；美拉托宁；退黑素；N-乙酰-5-甲氧基色胺；褪黑色素；松果素；褪黑激素；3-N-乙酰基-5-甲氧基色胺；松果体素；美乐托宁；麦乐通宁；松果腺素
• 英文名称: 5-methoxy-N-acetyl-tryptamine
• 英文别名: melatonin；N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide；melatonine；N-acetyl-5-methoxytryptamine；MLT；N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide
• CAS: 73-31-4
• 化学式: C₁₃H₁₆N₂O₂
• mdl: MFCD00005655
• 分子量: 232.282
• InChiKey: DRLFMBDRBRZALE-UHFFFAOYSA-N

物化性质

• 熔点：
  116.5-118 °C (lit.)
• 沸点：
  374.44°C (rough estimate)
• 密度：
  1.1099 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  溶于乙醇至少50mg/ml
• LogP：
  1.043 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Pale yellow leaflets from benzene
• 蒸汽压力：
  1.4X10-7 mm Hg at 25 °C (est)
• 解离常数：
  Melatonin has pKa of 16.51 and -0.69 and is uncharged in the entire pH-range
• 碰撞截面：
  154.3 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]
• 保留指数：
  2451.9

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  2

ADMET

代谢

在肝脏中代谢至少产生14种已识别的代谢物（在小鼠尿液中发现）：6-羟基褪黑素葡萄糖苷酸、6-羟基褪黑素硫酸盐、N-乙酰血清素葡萄糖苷酸、N-乙酰血清素硫酸盐、6-羟基褪黑素、2-氧褪黑素、3-羟基褪黑素、褪黑素葡萄糖苷酸、环状褪黑素、环状N-乙酰血清素葡萄糖苷酸、环状6-羟基褪黑素、5-羟基吲哚-3-乙醛、二羟基褪黑素及其葡萄糖苷酸结合物。在小鼠尿液中，6-羟基褪黑素葡萄糖苷酸是主要的代谢物（占尿液中褪黑素代谢物总量的65-88%）。

Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).

来源:DrugBank

代谢

大多数循环中的褪黑素在肝脏中被灭活，首先通过一种依赖P450的微粒体氧化酶被氧化成6-羟基褪黑素，然后大部分与硫酸或葡萄糖醛酸结合，在排入尿液或粪便之前。

Most of the melatonin in the circulation is inactivated in the liver where it is first oxidized to 6-hydroxy melatonin by a P450-dependent microsomal oxidase and then largely conjugated to sulfate or glucuronide before being excreted into urine or feces.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人中，松果体激素褪黑素（MEL）主要被代谢为6-羟基褪黑素（6-HMEL），然后与硫酸盐结合并从尿液中排出。MEL的O-去甲基化代表了一个较小的反应。个体人类细胞色素P450（P450s）在这些途径中的确切作用尚未确定。作者使用了11种重组人类P450同工酶的阵列，首次研究了MEL的6-羟基化和O-去甲基化。CYP1A1、CYP1A2和CYP1B1都进行了MEL的6-羟基化，CYP2C19起到了较小的作用。这些反应是NADPH依赖性的。CYP2C19以及在一定程度上CYP1A2对MEL进行了O-去甲基化。6-羟基化的K(m)（微摩尔）和V(max)（k(cat)，pmol/分钟/ pmol P450）的估计值为19.2 ± 2.01和6.46 ± 0.22（CYP1A1）、25.9 ± 2.47和10.6 ± 0.32（CYP1A2）以及30.9 ± 3.76和5.31 ± 0.21（CYP1B1）。这些发现证实了其他人的建议，即CYP1A2很可能是MEL的6-羟基化中的主要肝脏P450，以及一份报告表明CYP1A1也能介导这个反应。然而，这是首次显示CYP1B1能够6-羟基化MEL。对于CYP1B1选择性抑制剂（E）-2,4,3',5'-四甲氧基芪的IC50估计为30 nM，用于重组人类CYP1B1的MEL 6-羟基化。比较野生型和cyp1b1-null小鼠的大脑匀浆发现，MEL的6-羟基化明显在很大程度上由CYP1B1介导。CYP1B1不在肝脏表达，但具有普遍的肝外分布，并且在也积累MEL或6-HMEL的组织中含量较高，如肠道和大脑皮层，它可能有助于调节MEL和6-HMEL的水平。

In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. /The authors/ used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, O-demethylated MEL. The K(m) (uM) and V(max) (k(cat), pmol/ min/ pmol P450) for 6-hydroxylation were estimated as 19.2 +/- 2.01 and 6.46 +/- 0.22 (CYP1A1), 25.9 +/- 2.47 and 10.6 +/- 0.32 (CYP1A2), and 30.9 +/- 3.76 and 5.31 +/- 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1-selective inhibitor (E)-2,4,3',5'-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.

来源:Hazardous Substances Data Bank (HSDB)

代谢

褪黑素在夜间由人类的松果体合成并释放到血液和脑脊液中。它作用于人类大脑，促进睡眠，并影响睡眠和多种其他昼夜节律的相位。在白天，血浆中褪黑素的水平较低；而在夜间，年轻成年人的褪黑素水平会上升10到100倍甚至更多，但老年人的上升幅度则小得多，他们经常可能会有频繁的夜间觉醒作为结果。非常小的口服剂量褪黑素就能将白天的血浆褪黑素水平提高到夜间水平，从而使得人们在下午或晚上更容易入睡。这样的剂量还可以帮助老年人在夜间保持睡眠。褪黑素还被偶尔声称具有其他医疗益处，例如预防动脉硬化、癌症和阿尔茨海默症等与年龄相关的疾病。但这类说法的证据是稀少的。

Melatonin is synthesized at night in the human pineal gland and released into the blood and cerebrospinal fluid. It acts on the brains of humans to promote sleep, and also influences the phasing of sleep and various other circadian rhythms. During the day, plasma melatonin levels are low; at night, they rise 10 to 100-fold or more in young adults, but by considerably less in older people- who often may have frequent nocturnal awakenings as a consequence. Very small oral doses of melatonin raise daytime plasma melatonin to night-time levels, thus making it easier for people to fall asleep in the afternoon or evening. Such doses can also help older people remain asleep during the night. Melatonin has also occasionally been claimed to confer other medical benefits e.g. preventing such age-related diseases as atherosclerosis, cancer, and alzheimer's disease. The evidence in such claims is sparse.

来源:Hazardous Substances Data Bank (HSDB)

代谢

褪黑激素已知的人类代谢物包括N-乙酰-5-羟基色胺、6-[3-(2-乙酰胺基乙基)-5-甲氧基吲哚-1-基]-3,4,5-三羟基氧杂环-2-羧酸和6-羟基褪黑激素。

Melatonin has known human metabolites that include N-Acetyl-5-hydroxytryptamine, 6-[3-(2-Acetamidoethyl)-5-methoxyindol-1-yl]-3,4,5-trihydroxyoxane-2-carboxylic acid, and 6-Hydroxymelatonin.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

褪黑素是色氨酸的衍生物。它能与褪黑素受体1A型结合，进而作用于腺苷酸环化酶和抑制cAMP信号转导途径。褪黑素不仅抑制腺苷酸环化酶，还能激活磷脂酶C。这增强了花生四烯酸的释放。通过与褪黑素受体1型和2型结合，下游的信号级联在体内产生各种效应。褪黑素受体是G蛋白偶联受体，在人体的各种组织中都有表达。人类受体的两个亚型是褪黑素受体1（MT1）和褪黑素受体2（MT2）。褪黑素和褪黑素受体激动剂，无论是在市场上还是在临床试验中，都能与并激活这两种受体类型。对激动剂与受体的结合研究已经进行了二十年，从1986年开始。这有些为人所知，但仍然没有完全理解。当褪黑素受体激动剂结合并激活其受体时，会引起许多生理过程。 MT1受体在中枢神经系统（CNS）的许多区域表达：下丘脑的视交叉上核（SNC）、海马、黑质、小脑、中枢多巴胺能途径、腹侧被盖区和伏隔核。MT1还表达在视网膜、卵巢、睾丸、乳腺、冠脉循环和主动脉、胆囊、肝脏、肾脏、皮肤和免疫系统。MT2受体主要在CNS中表达，也存在于肺、心脏、冠脉和主动脉组织、子宫肌层和颗粒细胞、免疫细胞、十二指肠和脂肪细胞中。 褪黑素与褪黑素受体的结合激活了几种信号通路。MT1受体激活抑制腺苷酸环化酶，其抑制会引起一系列非激活的涟漪效应；从减少环状腺苷酸单磷酸（cAMP）的形成开始，然后进展为较少的蛋白激酶A（PKA）活性，这反过来阻碍了cAMP反应元件结合蛋白（CREB结合蛋白）向P-CREB的磷酸化。MT1受体还激活磷脂酶C（PLC），影响离子通道并调节细胞内离子流量。褪黑素与MT2受体的结合抑制腺苷酸环化酶，减少cAMP的形成。[4]同时它也阻碍鸟苷酸环化酶，因此形成环状鸟苷酸单磷酸（cGMP）。与MT2受体的结合可能影响PLC，增加蛋白激酶C（PKC）的活性。受体的激活可能导致细胞内离子流量。

Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在几项临床试验中，褪黑素被发现具有良好的耐受性，并未与血清酶升高或肝脏损伤的证据相关联。尽管被广泛使用，褪黑素并未被确凿地与临床上明显的肝脏损伤案例联系在一起。 可能性评分：E（不太可能是临床上明显肝脏损伤的原因）。 药物类别：草药和膳食补充剂；镇静剂和催眠剂 该亚类药物中的其他药物，褪黑素及其类似物：雷美替隆，他司美琼。

In several clinical trials, melatonin was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite wide scale use, melatonin has not been convincingly linked to instances of clinically apparent liver injury. Likelihood score: E (unlikely cause of clinically apparent liver injury). Drug Class: Herbal and Dietary Supplements; Sedatives and Hypnotics Other Drugs in the Subclass, Melatonin and its Analogues: Ramelteon, Tasimelteon

来源:LiverTox

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

耐受性可能会发展，在这种情况下，人们需要更大剂量才能达到预期效果；这可能导致过量使用和死亡。由于副作用包括协调能力丧失、反应时间减慢、嗜睡和判断力受损，还可能发生意外或伤害。这类药物具有很高的身体和心理依赖潜力。可能会引起一种可能发展成史蒂文斯-约翰逊综合征的潜在危险皮疹，这是一种极为罕见但可能致命的皮肤病。

Tolerance can develop, in which the person needs larger doses to achieve the desired effect; this can lead to overdose and death. Accidents or injury can also occur due to the side effects of loss of coordination, slowed reaction time, sleepiness and impaired judgment. Drugs in this category have a high potential for physical and psychological dependence. May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：褪黑素是由松果体产生的激素，它在调节睡眠和昼夜节律以及可能在肠道-大脑信号传递中发挥作用。它是母乳的正常成分，夜间（大约凌晨3点达到峰值）的浓度高于白天。选择性剖宫产导致白天的初乳水平高于阴道分娩。一些作者建议，母亲应该在夜间在黑暗中哺乳，以避免母乳中褪黑素含量的减少，这可能会干扰婴儿的睡眠模式。还建议泵奶的母亲区分白天泵出的奶和夜间泵出的奶。一些研究将母乳喂养婴儿比配方奶喂养婴儿睡眠时间更长归因于母乳中的褪黑素。另一项研究发现，夜间初乳中的褪黑素水平较高，这似乎增加了初乳细胞对细菌的吞噬活性。一项针对329位母亲的调查发现，与直接母乳喂养、配方奶喂养、按时泵奶喂养和混合喂养的婴儿相比，食用时间不定的泵奶的婴儿入睡时间更长。母乳喂养的婴儿在夜间醒来的次数比食用时间不定的泵奶的婴儿多。 外源性给予褪黑素在母乳喂养期间没有特定用途，关于哺乳期母亲使用褪黑素的安全性的数据不存在。然而，剂量高于母亲补充后预期的母乳中的剂量已在婴儿中安全使用。哺乳母亲在晚上使用常规剂量的褪黑素不太可能对她的母乳喂养婴儿产生不利影响，尽管一些作者因为缺乏数据以及早产儿中相对较长的半衰期而不建议使用。 膳食补充剂不需要美国食品药品管理局的广泛市场前批准。制造商负责确保产品的安全性，但在市场推广前不需要证明膳食补充剂的安全性和有效性。膳食补充剂可能含有多种成分，标签上标注的成分或其数量与实际成分或数量之间经常存在差异。制造商可以与独立组织签订合同，以验证产品或其成分的质量，但这并不证明产品的安全性和有效性。由于上述问题，一个产品的临床测试结果可能不适用于其他产品。有关膳食补充剂的更详细信息可以在LactMed网站的其它地方找到。 在Holder巴氏杀菌（62.5°C，30分钟）后，母乳中的褪黑素浓度保持不变。 ◉ 对母乳喂养婴儿的影响：一项针对54名仅母乳喂养的婴儿（n=54）、配方奶喂养的婴儿（n=40）及其母亲的研究，就婴儿行为对母亲进行了问卷调查。测量了其中5位母亲的乳汁中的褪黑素。仅母乳喂养的婴儿发生绞痛的几率较低，烦躁发作的严重程度较低，夜间睡眠时间有延长的趋势。人乳中的褪黑素呈现出昼夜节律曲线，在所有人工乳中都无法测量到。 一名18个月大的母乳喂养婴儿从出生起就有出血发作。一项血小板聚集测试显示，婴儿在母乳喂养后血小板聚集减少。当婴儿禁食时，血小板聚集正常。该婴儿的母亲偶尔服用褪黑素（剂量未说明）帮助睡眠。停止服用褪黑素3个月后，婴儿的血小板聚集恢复正常，婴儿没有再出现出血发作。出血发作可能是由褪黑素引起的。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Melatonin is the hormone produced by the pineal gland that plays a role in regulating sleep and circadian rhythm as well as a possible role in gut-brain signaling. It is a normal component of breastmilk, with concentrations higher during nighttime (peak around 3 am) than daytime. Elective cesarean section results in higher daytime colostrum levels than with vaginal delivery. Some authors suggest that mothers should nurse in the dark at night in order to avoid reductions in the melatonin content of breastmilk, which could disturb infant sleep patterns. Differentiating milk pumped during the day from milk pumped during darkness has also been suggested for women pumping milk for their infants. Some studies have attributed longer sleep time in breastfed infant than in formula-fed infants to melatonin in breastmilk. Another study found higher colostrum melatonin levels at night which appeared to increase the phagocytic activity of colostral cells against bacteria. A survey of 329 mothers found that infants who consumed mistimed expressed breastmilk took longer to get to sleep compared with infants who were directly breastfed, formula fed, fed timed expressed breast milk and fed breast milk/formula combined. Breastfed infants had more awakenings at night compared with infants who consumed mistimed expressed breastmilk. Exogenous administration of melatonin has no specific use during breastfeeding and no data exist on the safety of maternal use of melatonin during breastfeeding. However, doses higher than those expected in breastmilk after maternal supplementation have been used safely in infants. It is unlikely that short-term use of usual doses of melatonin in the evening by a nursing mother would adversely affect her breastfed infant, although some authors recommend against its use in breastfeeding because of the lack of data and a relatively long half-life in preterm neonates. Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products. More detailed information about dietary supplements is available elsewhere on the LactMed Web site. The concentration of melatonin in breastmilk is unchanged after Holder pasteurization (62.5 degrees C for 30 minutes). ◉ Effects in Breastfed Infants:A study on 54 exclusively breastfed infants (n = 54), formula-fed infants (n = 40) and their mothers questioned their mothers regarding infant behavior. Melatonin was measured in the milk of 5 of the mothers. Exclusively breastfed infants had a lower incidence of colic attacks, lower severity of irritability attacks, and a trend for longer nocturnal sleep duration. Melatonin in human milk showed a circadian curve and was unmeasurable in all artificial milks. An 18-month-old breastfed infant was having bleeding episodes since birth. A platelet aggregation test showed that the infant had reduced platelet aggregation after breastfeeding. When the infant was fasting, platelet aggregation was normal. The infant's mother was occasionally taking melatonin (dose not stated) for sleep. After she stopped melatonin intake for 3 months, the infant's platelet aggregation was normal and the infant had no further bleeding episodes. The bleeding episodes were possibly caused by melatonin. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

吸收、分配和排泄

• 吸收

褪黑素的吸收和生物利用度差异很大。

The absorption and bioavailability of melatonin varies widely.

来源:DrugBank

吸收、分配和排泄

为了确定褪黑素药代动力学是否在青春期发生变化，研究者对9名青春期前儿童、8名青春期少年和16名成人进行了静脉注射褪黑素，并测量了血清和唾液中褪黑素的含量以及尿液中6-羟基褪黑素硫酸盐的水平。初步研究发现，3名成人男性在0.1、0.5和5.0微克/公斤的剂量下，褪黑素的剂量线性关系良好，没有饱和动力学，代谢和尿液排泄未改变。所有其他受试者接受了0.5微克/公斤的褪黑素。根据血清褪黑素计算出的药代动力学参数显示，在成人中没有显著的性别差异。然而，在青春期前儿童和成人之间的发展差异是显著的，终末消除速率常数（1.08 +/- 0.25 对比 0.89 +/- 0.11 每小时），消除半衰期（0.67 +/- 0.12 对比 0.79 +/- 0.10 小时）以及浓度-时间曲线下的面积（250.9 +/- 91.8 对比 376.9 +/- 154.3 (pg/mL)小时）分别有差异。在所有时间点，血清中的褪黑素水平高于唾液，血清和唾液褪黑素的比例在个体内和个体间可变化高达55倍。基于唾液褪黑素的结果显示，青春期前儿童和成人在终末消除速率常数上存在显著差异（1.90 +/- 0.95 对比 1.06 +/- 0.28 每小时）。所描述的药代动力学参数的组间差异表明，青春期前儿童比成人更快地代谢褪黑素。血清和唾液褪黑素之间的不一致比例呼吁在药代动力学研究或推断松果体功能时谨慎使用唾液褪黑素。目前的研究结果提示，结合已知的血清褪黑素随年龄下降以及青春期前儿童更高的代谢物排泄率，我们可以得出结论，青春期前松果体的褪黑素分泌率高于成人。

To determine whether melatonin pharmacokinetics change during puberty, ... melatonin /was infused/ iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and melatonin in serum and saliva and 6-hydroxymelatonin sulfate in urine /were measured/. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 ug/kg. All other subjects received 0.5 ug/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 per hr), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 hr), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL)hr, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 per hr). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

日间服用褪黑激素的药代动力学已在4名健康受试者单次静脉注射5或10微克/人以及6名健康受试者连续5小时静脉输注20微克/人的情况下进行了研究。此外，还对一名松果体切除患者进行了研究，该患者的夜间血浆褪黑激素已被消除，研究是在夜间和日间各进行一次静脉输注后进行的。褪黑激素从血液中的清除显示出双指数衰减。除消失速率常数β和稳态表观分布体积（Vss）外，两项研究中的药代动力学参数相似。在平台期和下降部分的轮廓上叠加了额外的峰值或谷值。它们不是由于内源性分泌的刺激引起的，因为松果体切除患者也出现了这些现象。在褪黑激素输注期间，血浆激素水平在60和120分钟后达到稳态，并且与夜间水平相当。

The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 ug/person and after a 5 hr infusion of 20 ug per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项随机双盲对照研究中，10名健康男性受试者进行了80分钟的高强度肌肉肥大性重阻力训练（RES），主要锻炼下肢和上肢的主要肌肉。受试者在两次实验中分别随机接受褪黑素（6毫克）或安慰剂（6毫克），每次RES前60分钟服用。在早晨空腹状态和RES前（前60分钟，前0分钟）、RES期间（中间）以及RES后（后0分钟，后15分钟，后30分钟，后60分钟）从肘前静脉抽取血液样本。... 在服用褪黑素后，褪黑素组的血清褪黑素浓度显著增加（P<0.05-0.001），并在之后每个时间点都保持升高。浓度在服用后60分钟达到峰值，为1171.3+/-235.2 pg/mL。在安慰剂组中，血清褪黑素浓度在RES前、RES中和RES后（后0分钟，后15分钟）也略有但显著增加（P<0.05）。在所有时间点，两组之间的血清褪黑素浓度存在较大差异（P<0.01-0.001）。

... In a randomized and double-blind controlled study 10 healthy male subjects undertook an 80 min intensive hypertrophic heavy resistance exercise session (RES) for major muscles of the lower and upper extremities. The subjects were studied on two occasions receiving either melatonin (6 mg) or placebo (6 mg) in random order 60 min before each RES. Blood samples were taken from an antecubital vein both in fasting conditions in the morning and before RES (pre 60 min, pre 0 min), during RES (middle) and after RES (post 0 min, post 15 min, post 30 min, post 60 min). ... The serum melatonin concentration increased significantly (P<0.05-0.001) in the melatonin group following oral ingestion of melatonin and was elevated at every time point after that. The concentration reached a peak value of 1171.3+/-235.2 pg/mL in 60 min at pre 0. Serum melatonin increased slightly but significantly (P<0.05) also in the placebo group just before RES, in the middle of RES and after RES (post 0, post 15). There were large differences (P<0.01-0.001) in the serum melatonin concentration between the groups at all time points. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

研究了在大鼠、狗和猴子静脉注射和口服给药后褪黑激素的药代动力学，并从血浆浓度-时间曲线下面积计算了褪黑激素的绝对口服生物利用度。静脉注射3 mg/kg（大鼠为5 mg/kg）褪黑激素后，褪黑激素的表观消除半衰期分别为大鼠19.8分钟，狗18.6分钟，猴子34.2分钟。大鼠口服10 mg/kg剂量后，褪黑激素的剂量标准化口服生物利用度为53.5%，而在狗和猴子中则超过了100%。此外，大鼠腹腔注射10 mg/kg褪黑激素的生物利用度为74.0%，这表明大鼠中褪黑激素的首次通过肝脏提取作用不大。然而，狗在口服1 mg/kg剂量后，褪黑激素的口服生物利用度降低到了16.9%，这表明狗的褪黑激素生物利用度具有剂量依赖性。

...Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S24/25
• 危险类别码：
  R60
• WGK Germany：
  2
• 海关编码：
  2932999099
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  AC5955000
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  请将储存于阴凉干燥处。保存于此。

SDS

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模块 1. 化学品
1.1 产品标识符
: 褪黑素
产品名称
1.2 鉴别的其他方法
N-Acetyl-5-methoxytryptamine
1.3 有关的确定了的物质或混合物的用途和建议不适合的用途
仅用于研发。不作为药品、家庭或其它用途。

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模块 2. 危险性概述
2.1 GHS-分类
急性毒性, 经口 (类别 5)
2.2 GHS 标记要素，包括预防性的陈述
象形图 无
警示词 警告
危险申明
H303 吞咽可能有害。
警告申明
事故响应
P312 如感觉不适，呼救中毒控制中心或医生.
2.3 其它危害物 - 无

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模块 3. 成分/组成信息
3.1 物 质
: N-Acetyl-5-methoxytryptamine
别名
: C13H16N2O2
分子式
: 232.28 g/mol
分子量
组分 浓度或浓度范围
N-(2-(5-methoxyindol-3-yl)ethyl)acetamide
<=100%
化学文摘登记号(CAS 73-31-4
No.) 200-797-7
EC-编号

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模块 4. 急救措施
4.1 必要的急救措施描述
一般的建议
请教医生。 向到现场的医生出示此安全技术说明书。
吸入
如果吸入,请将患者移到新鲜空气处。 如呼吸停止,进行人工呼吸。 请教医生。
皮肤接触
用肥皂和大量的水冲洗。 请教医生。
眼睛接触
用水冲洗眼睛作为预防措施。
食入
切勿给失去知觉者通过口喂任何东西。 用水漱口。 请教医生。
4.2 主要症状和影响，急性和迟发效应
据我们所知，此化学，物理和毒性性质尚未经完整的研究。
4.3 及时的医疗处理和所需的特殊处理的说明和指示
无数据资料

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模块 5. 消防措施
5.1 灭火介质
灭火方法及灭火剂
用水雾,抗乙醇泡沫,干粉或二氧化碳灭火。
5.2 源于此物质或混合物的特别的危害
碳氧化物, 氮氧化物
5.3 给消防员的建议
如必要的话,戴自给式呼吸器去救火。
5.4 进一步信息
无数据资料

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模块 6. 泄露应急处理
6.1 作业人员防护措施、防护装备和应急处置程序
使用个人防护用品。 避免粉尘生成。 避免吸入蒸气、烟雾或气体。 避免吸入粉尘。
6.2 环境保护措施
不要让产品进入下水道。
6.3 泄漏化学品的收容、清除方法及所使用的处置材料
收集和处置时不要产生粉尘。 扫掉和铲掉。 放入合适的封闭的容器中待处理。
6.4 参考其他部分
丢弃处理请参阅第13节。

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模块 7. 操作处置与储存
7.1 安全操作的注意事项
避免形成粉尘和气溶胶。
在有粉尘生成的地方,提供合适的排风设备。
7.2 安全储存的条件,包括任何不兼容性
贮存在阴凉处。 使容器保持密闭，储存在干燥通风处。
建议的贮存温度： -20 °C
保存在干燥处。
7.3 特定用途
无数据资料

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模块 8. 接触控制和个体防护
8.1 容许浓度
最高容许浓度
没有已知的国家规定的暴露极限。
8.2 暴露控制
适当的技术控制
根据良好的工业卫生和安全规范进行操作。 休息前和工作结束时洗手。
个体防护设备
眼/面保护
请使用经官方标准如NIOSH (美国) 或 EN 166(欧盟) 检测与批准的设备防护眼部。
皮肤保护
戴手套取 手套在使用前必须受检查。
请使用合适的方法脱除手套(不要接触手套外部表面),避免任何皮肤部位接触此产品.
使用后请将被污染过的手套根据相关法律法规和有效的实验室规章程序谨慎处理. 请清洗并吹干双手
所选择的保护手套必须符合EU的89/686/EEC规定和从它衍生出来的EN 376标准。
身体保护
根据危险物质的类型，浓度和量，以及特定的工作场所选择身体保护措施。,
防护设备的类型必须根据特定工作场所中的危险物的浓度和数量来选择。
呼吸系统防护
不需要保护呼吸。如需防护粉尘损害，请使用N95型（US）或P1型（EN 143)防尘面具。
呼吸器使用经过测试并通过政府标准如NIOSH（US）或CEN（EU）的呼吸器和零件。

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模块 9. 理化特性
9.1 基本的理化特性的信息
a) 外观与性状
形状: 粉末
颜色: 白色, 灰白色或米色
b) 气味
无数据资料
c) 气味阈值
无数据资料
d) pH值
无数据资料
e) 熔点/凝固点
熔点/凝固点: 116.5 - 118 °C - lit.
f) 沸点、初沸点和沸程
无数据资料
g) 闪点
无数据资料
h) 蒸发速率
无数据资料
i) 易燃性(固体,气体)
无数据资料
j) 高的/低的燃烧性或爆炸性限度 无数据资料
k) 蒸气压
无数据资料
l) 蒸汽密度
无数据资料
m) 密度/相对密度
无数据资料
n) 水溶性
无数据资料
o) n-辛醇/水分配系数
无数据资料
p) 自燃温度
无数据资料
q) 分解温度
无数据资料
r) 粘度
无数据资料

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模块 10. 稳定性和反应活性
10.1 反应性
无数据资料
10.2 稳定性
无数据资料
10.3 危险反应
无数据资料
10.4 应避免的条件
发光。
10.5 不相容的物质
强氧化剂
10.6 危险的分解产物
其它分解产物 - 无数据资料

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模块 11. 毒理学资料
11.1 毒理学影响的信息
急性毒性
半数致死剂量 (LD50) 经口 - 大鼠 - > 3,200 mg/kg
皮肤刺激或腐蚀
无数据资料
眼睛刺激或腐蚀
无数据资料
呼吸道或皮肤过敏
无数据资料
生殖细胞致突变性
无数据资料
致癌性
IARC:
此产品中没有大于或等于 0。1%含量的组分被 IARC鉴别为可能的或肯定的人类致癌物。
生殖毒性
从实验动物的结果看，过度接触能导致生殖紊乱
特异性靶器官系统毒性（一次接触）
无数据资料
特异性靶器官系统毒性（反复接触）
无数据资料
吸入危险
无数据资料
潜在的健康影响
吸入 吸入可能有害。 可能引起呼吸道刺激。
摄入 如服入是有害的。
皮肤 通过皮肤吸收可能有害。 可能引起皮肤刺激。
眼睛 可能引起眼睛刺激。
接触后的征兆和症状
据我们所知，此化学，物理和毒性性质尚未经完整的研究。
附加说明
化学物质毒性作用登记: AC5955000

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模块 12. 生态学资料
12.1 生态毒性
无数据资料
12.2 持久性和降解性
无数据资料
12.3 潜在的生物累积性
无数据资料
12.4 土壤中的迁移性
无数据资料
12.5 PBT 和 vPvB的结果评价
无数据资料
12.6 其它不良影响
无数据资料

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模块 13. 废弃处置
13.1 废物处理方法
产品
将剩余的和不可回收的溶液交给有许可证的公司处理。
与易燃溶剂相溶或者相混合，在备有燃烧后处理和洗刷作用的化学焚化炉中燃烧
受污染的容器和包装
按未用产品处置。

---

模块 14. 运输信息
14.1 联合国危险货物编号
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.2 联合国运输名称
欧洲陆运危规: 非危险货物
国际海运危规: 非危险货物
国际空运危规: 非危险货物
14.3 运输危险类别
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.4 包裹组
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.5 环境危险
欧洲陆运危规: 否 国际海运危规 国际空运危规: 否
海洋污染物（是/否）: 否
14.6 对使用者的特别提醒
无数据资料

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模块 15 - 法规信息
N/A

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模块16 - 其他信息
N/A

制备方法与用途

这段文本详细介绍了松果体及其分泌物——褪黑素的相关信息，主要包含以下几个方面：

1. 定义与来源：褪黑素是由大脑中的松果体分泌的一种激素，它存在于哺乳动物的松果体中。褪黑素是一种白色或类白色的结晶粉末。

2. 生理作用与影响：

   • 褪黑素对脑部的作用包括增强脑内某些神经递质（如γ-氨基丁酸和5-羟色胺）的含量，起到调整和镇静作用。
   • 在下丘脑和垂体中的作用：褪黑素可以调节促性腺激素、促甲状腺激素和黄体生成素等的分泌。
   • 对生殖系统的影响：松果体对性腺具有抑制作用，影响青春期和性早熟等问题。
   • 褪黑素还能影响甲状腺、肾上腺皮质以及胰岛的功能，如减少醛固酮分泌，增加糖耐量。

3. 合成与释放： 松果体细胞从血循环中摄取色氨酸，在特定酶的作用下转化为褪黑素。这个过程涉及到多个步骤的化学反应，最终形成的褪黑素可以进入血液或通过脑脊液进入血液循环。

4. 功能与应用：褪黑素不仅具有促进睡眠的功能（被称为“安眠药”），还被用于医药保健品中以增强人体免疫力、防止老化以及回复青春。此外，在生化研究中有重要用途，它在细胞凋亡路径上也有复杂的效应，能够抑制免疫细胞和神经元的凋亡同时增强癌细胞的凋亡。

5. 生产方法：褪黑素的传统提取方法是将牛的大脑松果体冷冻干燥后研磨成粉末，并通过石油醚脱脂处理。然后与去离子水混合形成浆状物，离心分离并用乙酸乙酯抽提纯化，最后真空干燥得到精制品。

这段内容全面介绍了褪黑素的功能、合成机制及其在医学和研究中的应用价值。

反应信息

• 作为反应物：
  描述：

  褪黑素 在 苯基三甲基溴化铵 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 2-溴褪黑素
  参考文献：
  名称：

  2-芳基褪黑激素类似物：探索褪黑激素 MT1 和 MT2 受体的 2-苯基结合口袋

  摘要：

  在褪黑激素 MT 1和 MT 2受体的晶体结构中，已经表征了容纳强效激动剂 2-苯基褪黑激素的苯环的亲脂性亚袋。该子口袋似乎是实现对 MT 2受体的高结合亲和力和选择性的关键结构元件。合成了一系列 2-芳基吲哚配体，以探索最佳占据和与 2-苯基结合口袋相互作用的要求。应用于与 α-萘基衍生物复合的MT 1和 MT 2受体的热力学积分模拟为 MT 2提供了理论基础-对几种阻转异构体的结合模式的选择性和研究允许定义子口袋内的可用空间和取代基的排列。有趣的是，更具亲水性的 2-氮杂取代化合物显示出高结合亲和力，分子动力学模拟强调了与可能导致其效力的亚袋残基的极性相互作用。

  DOI：

  10.1016/j.ejmech.2022.114762
• 作为产物：
  描述：

  N-(2-{5-甲氧基-1-[(4-甲基苯基)磺酰基]-1H-吲哚-3-基}乙基)乙酰胺 在 N,N-二甲基丙烯基脲 、 三(2-氨基乙基)胺 、 cadmium sulphide 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以68%的产率得到褪黑素
  参考文献：
  名称：

  CdS 量子点作为有机化学的有效光还原剂，通过俄歇工艺实现

  摘要：

  强还原剂（相对于饱和甘汞电极（SCE）<−2.0 V）可实现多种有用的有机化学，但受到各种限制。这些反应通常采用化学计量的金属还原剂，例如碱金属和SmI 2 。然而，包括费用、易用性、安全性和废物产生在内的考虑因素限制了这些方法的实用性。最近利用多光子或电子引发的光氧化还原催化能量的方法已经获得了相当于 Li 0的还原电位并展示了这如何能够通过芳基自由基选择性转化芳基氯。然而，在某些情况下，催化中间体的稳定性较低可能会限制营业额。在此，我们报告了 CdS 纳米晶体量子点（QD）作为强光还原剂的能力，并提供了证据表明，通过中间还原猝灭的 CdS QD 的两次连续光激发产生高度还原电子。机械实验表明，俄歇复合（一种已知发生在光激发阴离子量子点中的光物理现象）会产生瞬态热激发电子，从而实现观察到的还原。使用蓝色发光二极管 (LED) 和牺牲胺还原剂、芳基氯和还原电位高达 -3 的磷酸酯。4 V vs

  DOI：

  10.1021/jacs.2c03235
• 作为试剂：
  描述：

  2',3'-O-isopropylidene-5-bromouridine 在 褪黑素 作用下， 以 乙腈 为溶剂， 反应 10.0h， 以13%的产率得到5-[3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl]-2',3'-O-(1-methylethylidene)uridine
  参考文献：
  名称：

  Acetone-sensitized photocoupling of 5-bromouridine to tryptophan derivatives via electron-transfer process

  摘要：

  DOI：

  10.1021/ja00545a024

文献信息

• [EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010104818A1

  公开（公告）日：2010-09-16

  MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-O 、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、- 、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、- 、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] QUINONE BASED NITRIC OXIDE DONATING COMPOUNDS<br/>[FR] COMPOSÉS DONNEURS D'OXYDE NITRIQUE À BASE DE QUINONE
  申请人：NICOX SA

  公开号：WO2013060673A1

  公开（公告）日：2013-05-02

  The present invention relates to nitric oxide donor compounds having a quinone based structure, to processes for their preparation and to their use in the treatment of pathological conditions where a deficit of NO plays an important role in their pathogenesis.

  本发明涉及具有喹诚基结构的一氧化氮供体化合物，涉及其制备方法以及它们在治疗病理状况中的应用，其中一氧化氮缺乏在它们的发病机制中起重要作用。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。

表征谱图