Lofentanil | 61380-40-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: Lofentanil
• 英文别名: methyl (3R,4S)-3-methyl-1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
• CAS: 61380-40-3；60645-00-3
• 化学式: C₂₅H₃₂N₂O₃
• 分子量: 408.5
• InChiKey: IMYHGORQCPYVBZ-NLFFAJNJSA-N

物化性质

• 颜色/状态：
  Solid
• 溶解度：
  In water, 0.6748mg/L at 25 °C (est)
• 蒸汽压力：
  3.5X10-10 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 8.36 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

毒理性

• 毒性总结

洛芬太尼是一种非常强效的阿片类止痛药。它在临床上用于疼痛管理。然而，这种药物的高止痛效力因长期使用后产生耐受性而受限。在患者研究中，非常低发生率的不良反应包括恶心、呕吐和镇静。另一项研究提到，三名患者出现嗜睡作为不良反应。在动物研究中，向大鼠静脉注射递增剂量的洛芬太尼（0、0.08、0.16、0.31、0.63、1.25、2.50、5.00 和 10.0 微克/千克），以检查中枢神经系统（CNS）抑制剂剂量、止痛程度（抑制尾撤反射）、麻醉（对骨碎伤无反应）和CNS阿片受体占有率之间的关系。递增剂量的洛芬太尼产生递增的止痛和麻醉效果，并最终达到阿片受体的完全占有率。当洛芬太尼的剂量（0.31 微克/千克）导致CNS阿片受体结合水平低到无法测量时，产生止痛效果，而当洛芬太尼的剂量（1.25 微克/千克）在大脑皮层和皮层下区域产生约25%的阿片受体占有率时，产生麻醉效果。在大鼠中，需要比麻醉剂量高八倍的洛芬太尼剂量（10.0 微克/千克）才能几乎饱和所有可用的CNS阿片受体。

IDENTIFICATION AND USE: Lofentanil is a very potent opioid analgesic. It is used clinically in the management of pain. However, the high analgesic potency of this drug is limited by the development of tolerance after chronic use. HUMAN STUDIES: In patients side effects of very low incidence included nausea, vomiting and sedation. Another study mentions drowsiness in three patients as a side effect. ANIMAL STUDIES: Increasing doses of lofentanil (0, 0.08, 0.16, 0.31, 0.63, 1.25, 2.50, 5.00, and 10.0 ug/kg) were administered intravenously to rats to examine the relationship among central nervous system (CNS) depressant dosage, degree of analgesia (inhibition of tail withdrawal reflex), anesthesia (no response to bone-crush injury), and CNS opiate-receptor occupancy. Increasing doses of lofentanil produce increasing analgesia and anesthesia and eventually complete opiate receptor occupancy. Analgesia occurs with doses of lofentanil (0.31 ug/kg) that result in levels of CNS opiate-receptor binding too low to be measured and anesthesia occurs with doses of lofentanil (1.25 ug/kg) that produce occupancy of about 25% of the available opiate receptors in subcortical areas and cortex. In rats a dose eight times the anesthetic dose of lofentanil is needed to saturate virtually all available CNS opiate receptors (10.0 ug/kg).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。必要时进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的呕吐反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施。1. 保持呼吸道通畅，必要时协助通气。给予补充氧气。如果出现昏迷、癫痫、低血压和非心源性肺水肿，则进行治疗。/阿片类药物和鸦片类药物/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-洛芬太尼，一种极具效力的阿片类药物，作用持续时间非常长，在大鼠迷走神经周围结扎后立即静脉注射。放射性物质在注射后24小时和48小时（更明显）在结扎处两侧积聚。相比之下，预先用纳洛酮处理的动物在坐骨神经结扎处或迷走神经两个结扎之间的区域没有积聚。在体外测量的特异性(3)H-洛芬太尼结合点的积聚仅在结扎上方，即神经的近端部分检测到。当在不同的时间间隔内结扎后注射(3)H-洛芬太尼时，我们观察到远端部分的标记急剧下降，近端部分也下降，但速度较慢。这可能是由于(3)H-洛芬太尼结合点的可能再循环或再利用。目前的数据与轴浆流动和静脉注射(3)H-洛芬太尼后体内标记的阿片受体可能再循环的情况相兼容。

(3)H-Lofentanil, an extremely potent opiate drug with a very long duration of action was injected intravenously into rats immediately after a ligature had been tied around the vagus nerve. Radioactivity accumulated on both sides of the ligature 24 hours and, to a larger extent, 48 hours after the injection. In contrast, there was no accumulation in animals pretreated with naloxone, neither in ligated sciatic nerves nor between two ligatures in the vagus nerve. An accumulation of stereospecific (3)H-lofentanil binding sites measured in vitro was only detected above the ligature, thus in the proximal part of the nerve. When (3)H-lofentanil was injected at different time intervals after ligation, we observed a tremendous drop of labelling in the distal and also but more slowly in the proximal part of the nerve. This could be due to a possible recycling or re-utilization of (3)H-lofentanil binding sites. The present data are compatible with an axoplasmic flow and a possible recycling of opiate receptors labelled in vivo after intravenous injection of (3)H-lofentanil.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(3)H-洛芬太尼在大鼠大脑各区域的体内结合情况进行了研究。静脉注射(3)H-洛芬太尼后，标记药物在大脑中的分布与体外结合实验测得的阿片受体区域分布完全平行。这种标记是可饱和的，如果在使用(3)H-洛芬太尼之前给予纳洛酮，可以在所有区域（除了小脑）防止标记。特定标记的长期存在与洛芬太尼极慢的解离速率和其长效作用完全相符。这解释了为什么(3)H-洛芬太尼在体内不能被纳洛酮置换。亚细胞分级实验揭示了前额皮质中的所有标记都是颗粒结合的，并且可以通过纳洛酮完全置换，而在小脑中则不是这样。(3)H-洛芬太尼在体内的优点是其极低的非特异性结合能力，以及能够揭示大脑中阿片受体非常低的占有率。

The in vivo binding of (3)H-lofentanil was studied in various regions of the brain in rat. After intravenous injection of (3)H-lofentanil the disposition of the labelled drug in the brain paralleled exactly the regional distribution of opiate receptors measured in in vitro binding assays. The labelling was saturable and could be prevented by naloxone when given before (3)H-lofentanil, in all the regions except in the cerebellum. The long-lasting occurrence of the specific labelling was entirely compatible with the extremely slow dissociation rate of lofentanil and its long duration of action. This explains why (3)H-lofentanil is not displaceable by naloxone in vivo. Subcellular fractionation experiments revealed that all the labelling in the frontal cortex but not in the cerebellum was particulate-bound and entirely displaceable by naloxone. The advantages of (3)H-lofentanil in vivo are its extremely low non-specific binding and its ability to reveal very low occupancy of opiate receptors in brain.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠、狗和健康志愿者中研究了芬太尼和三种类似物在体外的血浆蛋白结合和在血液中的分布。在人体血浆中，芬太尼的结合率为84.4%，舒芬太尼为92.5%，阿芬太尼为92.1%，洛芬太尼为93.6%。这四种镇痛药的血浆蛋白结合与其浓度在整个治疗范围内无关。阿芬太尼的血浆蛋白结合对pH的依赖性远小于其他三种镇痛药。注意到了“急性相”蛋白α1-酸性糖蛋白（α1-AGP）、脂蛋白和血细胞可能对芬太尼及其类似物在血液中的结合有所贡献。

The in vitro plasma protein binding and distribution in blood of fentanyl and three analogues were studied in rats, dogs and healthy volunteers. In human plasma, 84.4% of fentanyl was bound, 92.5% of sufentanil, 92.1% of alfentanil and 93.6% of lofentanil. Plasma protein binding of the four analgesics was independent of their concentration over the whole therapeutic range. Plasma protein binding of alfentanil was much less pH dependent than that of the three other analgesics. Attention was drawn to the possible contribution of the "acute phase" protein alpha 1-acid glycoprotein (alpha 1-AGP), of lipoproteins and of blood cells to the binding of fentanyl and its analogues in blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

孵化介质pH对豚鼠孤立心房细胞内三氚芬太尼、洛芬太尼和阿芬太尼积累的影响进行了研究。芬太尼和洛芬太尼在心房组织中分别积累了大约30倍和50倍。当达到平衡时，结合的药物量被发现依赖于介质的pH。通过绘制结合平衡与浴液pH的关系曲线，得到了类似于滴定曲线的曲线。在接近芬太尼和洛芬太尼的pKa值的pH值时，达到了一半的最大结合。阿芬太尼被发现积累较少。组织的摄取与细胞外浓度强烈成正比。在pH 8.5下与芬太尼平衡的心房，在暴露于pH 7.0时迅速释放该化合物，即使在浴液中持续存在芬太尼的情况下也是如此。根据这些发现，讨论了在体条件下的可能影响，特别是关于呼吸性酸中毒可能增强芬太尼作用的后果。

The influence of the pH of the incubation medium on the cellular accumulation of tritiated fentanyl, lofentanil, and alfentanil was investigated in isolated guinea pig atria. Fentanyl and lofentanil accumulated in atrial tissue up to about 30- and 50-fold, respectively. The amount of drug bound when equilibrium was attained was found to be dependent upon the pH of the medium. By plotting binding equilibria v. pH of the bath, curves were obtained which resembled titration curves. Half-maximal binding was attained at pH values close to the pKa values of fentanyl and lofentanil. Alfentanil was found to accumulate less. The uptake by the tissue was strongly proportional to the extracellular concentration. Atria equilibrated with fentanyl at pH 8.5 released the compound rapidly when exposed to a pH of 7.0, even in the continuous presence of fentanyl in the bath. The consequences of the findings for in vivo conditions are discussed with respect to a possible augmentation of the actions of fentanyl by respiratory acidosis.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• Sustained-release analgesic compounds
  申请人：——

  公开号：US20030022876A1

  公开（公告）日：2003-01-30

  A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.

  一种药理活性的创新化合物包括通过生理易降解的连接物共价连接的两个独立活性镇痛基团。一种首选实施例包括阿片类药物，如吗啡，通过生理易降解的连接物与来自阿片类或非阿片类化合物组成的群中选择的至少一种镇痛化合物共价连接。适当的共价连接物通过一个或多个内源的内酯、内酰胺或磺酰胺连接而与这两个独立活性的镇痛化合物共价结合。适当的连接物包括内源的羧酸酯、酰胺和磺酰胺基团，以及形成上述内酯、内酰胺或磺酰胺连接的外源基团。
• Controlled-release compositions containing opioid agonist and antagonist
  申请人：——

  公开号：US20020010127A1

  公开（公告）日：2002-01-24

  Controlled-release dosage forms containing an opioid agonist; an opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.

  含有阿片激动剂、阿片拮抗剂和受控释放材料的控释剂型，其在给药间隔期间释放阿片激动剂的镇痛或亚镇痛量以及足以减轻所述阿片激动剂的副作用的阿片拮抗剂的量。当给予人类患者时，该剂型提供至少约8小时的镇痛作用。在其他实施例中，给药间隔期释放的拮抗剂剂量增强了阿片激动剂的镇痛效力。
• [EN] COMBINATION THERAPY FOR PREVENTING ADDICTION<br/>[FR] POLYTHÉRAPIE POUR LA PRÉVENTION D'UNE ADDICTION
  申请人：AMYGDALA NEUROSCIENCES INC

  公开号：WO2019079209A1

  公开（公告）日：2019-04-25

  Disclosed is a novel combination therapy to reduce or prevent the acquisition of a conditioned response in a mammal comprising administering to the mammal a therapeutically effective amount of an aldehyde dehydrogenase (ALDH-2) inhibitor compound, such as a compound of Formula (I), in combination with a substance that produces the conditioned response, such as a medication containing a dopamine-producing agent such as an opioid, whereby the combination acts to reduce or prevent the acquisition of a conditioned response, and the deleterious side-effect of misuse, dependence, abuse, and/or addiction.

  揭示了一种新颖的联合疗法，用于减少或预防哺乳动物获得条件反射，包括向哺乳动物施用治疗有效量的醛脱氢酶（ALDH-2）抑制剂化合物，例如公式（I）中的化合物，与产生条件反射的物质结合，例如含有多巴胺生成剂的药物，如阿片类药物，从而使该组合作用于减少或预防条件反射的获得，以及滥用、依赖、滥用和/或成瘾的有害副作用。
• CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
  申请人：Cerulean Pharma Inc.

  公开号：US20130196906A1

  公开（公告）日：2013-08-01

  Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

  提供了关于使用CDP-治疗剂偶联物治疗疾病或紊乱的方法，例如自身免疫疾病、炎症性疾病、中枢神经系统紊乱、心血管疾病或代谢紊乱。还提供了CDP-治疗剂偶联物、包含CDP-治疗剂偶联物的颗粒以及包含CDP-治疗剂偶联物的组合物。
• [EN] BUPRENORPHINE ANALOGS<br/>[FR] ANALOGUES DE BUPRÉNORPHINE
  申请人：PURDUE PHARMA LP

  公开号：WO2012038813A1

  公开（公告）日：2012-03-29

  The present invention is directed to Buprenorphine Analog compounds of the Formula (I), Formula (IA) or Formula (IB) shown below, wherein R1, R2, R8, R 3a, R 3b, G, X, Z and Y are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

  本发明涉及如下所示的公式(I)、公式(IA)或公式(IB)的丁丙诺啡类似物化合物，其中R1、R2、R8、R 3a、R 3b、G、X、Z和Y的定义如本文所述。本发明的化合物可用于治疗疼痛、便秘以及通过阿片类和ORL-1受体的活性调节的其他状况。