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Developmental potential for endomorphin opioidmimetic drugs. 类阿片药物内啡肽的发展潜力。
Pub Date : 2012-01-01 Epub Date: 2012-06-15 DOI: 10.1155/2012/715123

Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr(1) with 2',6'-dimethyl-l-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt(1)]EM-1 and [Dmt(1)]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt(1)]EM-1 (47) and [N-allyl-Dmt(1)]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier.

吗啡是μ-阿片受体的激动剂,几千年来一直被用作止痛药。阿片类拮抗剂,纳洛酮和纳曲酮,从吗啡中提取,用于药物成瘾和酒精滥用。然而,这些外源性激动剂和拮抗剂表现出许多不可接受的副作用。内源性阿片肽中,内啡肽(EM)-1和内啡肽(EM)-2具有较高的μ受体亲和力和相对于δ和κ受体的高选择性,为制备阿片类药物提供了充分的序列柔性实体。我们利用内啡肽的这一独特特性,将n端残基Tyr(1)与2',6'-二甲基-l-酪氨酸(Dmt)交换,以提高其稳定性和生物活性谱。我们系统地改变了[Dmt(1)]EM-1和[Dmt(1)]EM-2的特定残基,以产生各种类似物。在这些类似物中,[n -烯丙基- dmt (1)]EM-1(47)和[n -烯丙基- dmt (1)]EM-2(48)对μ受体表现出有效和选择性的拮抗作用:它们完全抑制纳洛酮和纳曲酮诱导的小鼠急性吗啡依赖后的戒断,并逆转酒精诱导的海马sIPSC切片的变化。总的来说,我们开发了新型有效的阿片类药物,没有有害的副作用,能够抵抗酶降解,并且很容易完整地通过胃肠道和血脑屏障的上皮膜运输。
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引用次数: 4
The Fate of Sulfamethazine in Sodium-Hypochlorite-Treated Drinking Water: Monitoring by LC-MS (n) -IT-TOF. 次氯酸钠处理的饮用水中磺胺乙嗪的归宿:LC-MS (n) -IT-TOF监测。
Pub Date : 2012-01-01 Epub Date: 2012-05-15 DOI: 10.1155/2012/693903

Pharmaceutical compounds represent a rapidly emerging class of environmental contaminants. Such compounds were recently classified by the U.S. Geological Survey, including several antibiotics. An LC-MS/MS screening method for the top five antibiotics in drinking water was developed and validated using a Shimadzu LC-MS-IT-TOF. The separation was performed using a Waters Acquity UPLC BEH C18 column with a gradient elution. Sulfamethazine was exposed to conditions intended to mimic drinking water chlorination, and samples were collected and quenched with excess sodium sulfite. Kinetics of sulfamethazine degradation was followed as well as the formation of the major chlorinated byproduct (m/z 313). For the screening method, all five antibiotic peaks were baseline resolved within 5 minutes. Additionally, precision and accuracy of the screening method were less than 15%. Degradation of sulfamethazine upon exposure to drinking water chlorination occurred by first order kinetics with a half-life of 5.3 × 10(4) min (approximately 37 days) with measurements starting 5 minutes after chlorination. Likewise, the formation of the major chlorinated product occurred by first order kinetics with a rate constant of 2.0 × 10(-2). The proposed identification of the chlorinated product was 4-amino-(5-chloro-4,6-dimethyl-2-pyrimidinyl)-benzenesulfonamide (C12H13N4O2SCl) using MS (n) spectra and databases searches of SciFinder and ChemSpider.

药物化合物是一类迅速出现的环境污染物。美国地质调查局最近对这类化合物进行了分类,其中包括几种抗生素。建立了饮用水中前5种抗生素的LC-MS/MS筛选方法,并采用岛津LC-MS- it - tof进行了验证。采用Waters Acquity UPLC BEH C18色谱柱进行分离,梯度洗脱。磺胺乙嗪暴露在模拟饮用水氯化的条件下,收集样品并用过量的亚硫酸钠淬火。研究了磺胺乙嗪的降解动力学以及主要氯化副产物(m/ z313)的形成。对于筛选方法,所有五个抗生素峰均在5分钟内基线解决。此外,筛选方法的精密度和准确度均小于15%。磺胺乙嗪暴露于饮用水氯化后的降解是一级动力学,半衰期为5.3 × 10(4) min(约37天),在氯化后5分钟开始测量。同样,主要氯化产物的形成是一级动力学,速率常数为2.0 × 10(-2)。通过质谱分析和SciFinder、ChemSpider数据库的检索,确定氯化产物为4-氨基-(5-氯-4,6-二甲基-2-嘧啶基)-苯磺酰胺(C12H13N4O2SCl)。
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引用次数: 11
Syntheses and in vitro biological activity of some derivatives of C-9154 antibiotic. C-9154抗生素衍生物的合成及体外生物活性研究。
Pub Date : 2012-01-01 Epub Date: 2012-11-25 DOI: 10.1155/2012/782058

In our continued attempts at designing new antibiotics based on the structure of the C-9154 antibiotic, to simultaneously improve activity and lower toxicity, an analogue to the C-9154 antibiotic and six derivatives of this analogue were synthesized. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were synthesized using a two-step reaction which involved an additional reaction between benzyl amine and maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride mediated esterification reaction. The compounds were fully characterized using Infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogues as was anticipated with minimum inhibitory concentration in the range 0.625-5 μg/mL. The analogue had minimum inhibitory concentration in the range 2.5-10 μg/mL. These values are significantly better than that obtained for the original C-9154 antibiotic which had activity in the range 10->100 μg/mL.

在我们基于C-9154抗生素结构设计新抗生素的持续尝试中,为了同时提高活性和降低毒性,我们合成了C-9154抗生素的类似物和该类似物的六个衍生物。该方法是通过将高极性羧基转化为酯官能团来显著降低衍生物中合成类似物的极性,从而增加细胞膜的通透性。该化合物的合成采用两步反应,即苯胺和马来酸酐之间的附加反应,然后通过亚硫酰氯介导的酯化反应将末端羧酸官能团转化为酯官能团。通过红外、气相色谱-质谱、一维和二维核磁共振实验对化合物进行了表征。化合物的体外生物活性表明,衍生物的活性高于类似物,最低抑制浓度在0.625 ~ 5 μg/mL之间。该类似物的最低抑菌浓度为2.5 ~ 10 μg/mL。这些值明显优于原抗生素C-9154的活性范围在10 ~ >100 μg/mL。
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引用次数: 4
Secondary Structural Preferences of Some Antibacterial Cyclooctapeptides in the Presence of Calcium(II). 钙(II)存在时某些抗菌环八肽的二级结构偏好。
Pub Date : 2012-01-01 Epub Date: 2012-12-18 DOI: 10.1155/2012/730239

The purpose of this study is to understand the interactions of some antibacterial cationic amphipathic cyclooctapeptides with calcium(II) and their secondary structural preferences. The thermodynamic parameters associated with calcium(II) interactions, between the antibacterial active cyclooctapeptides (COP 1-6) and those that did not exhibit significant activities (COP 7-9), were studied by isothermal titration calorimetry. Calcium(II) binding in the absence and presence of micellar dodecylphosphocholine (DPC), a membrane mimicking detergent, was conducted by circular dichroism (CD). Both groups of cyclopeptides showed weak binding affinities for calcium(II) (Kb ca. 10(-3) M(-1)). However, CD data showed that the antimicrobial peptides COP 1-6 adopted a twisted beta-sheet structure (positive CD absorption band at ca. 203 nm) in the presence of calcium(II) in micellar DPC. In contrast, COP 7-9, which lacked antibacterial activity, adopted a different conformational structure (negative CD absorption band at ca. 203 nm). These results indicate that these cyclopeptides could adopt secondary structural preferences in the presence of calcium(II) amidst a hydrophobic environment to elicit their antibacterial activity. These findings could be useful in facilitating the design of cyclopeptide derivatives that can adopt this beta-sheet-like secondary structure and, thereby, provide a useful molecular template for crafting antibacterial compounds.

本研究的目的是了解一些抗菌阳离子两性环八肽与钙(II)的相互作用及其二级结构偏好。通过等温滴定量热法研究了抗菌活性环八肽(COP 1-6)与无明显活性环八肽(COP 7-9)之间与钙(II)相互作用相关的热力学参数。在没有和有胶束十二烷基磷酸胆碱(DPC)(一种膜模拟洗涤剂)的情况下,通过圆二色性(CD)测定了钙(II)的结合情况。两组环肽对钙(II)的结合亲和力都很弱(Kb 约为 10(-3) M(-1))。然而,CD 数据显示,抗菌肽 COP 1-6 在胶束 DPC 中与钙(II)存在时采用了扭曲的β-片状结构(约 203 nm 处的正 CD 吸收带)。相反,缺乏抗菌活性的 COP 7-9 则采用了不同的构象结构(约 203 纳米波长处的负 CD 吸收带)。这些结果表明,这些环肽在钙(II)存在的疏水环境中可以采用二级结构选择来激发其抗菌活性。这些发现有助于设计出能够采用这种β片状二级结构的环肽衍生物,从而为制作抗菌化合物提供有用的分子模板。
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引用次数: 0
AutoGPA: An Automated 3D-QSAR Method Based on Pharmacophore Alignment and Grid Potential Analysis. AutoGPA:基于药层排列和网格电位分析的自动 3D-QSAR 方法。
Pub Date : 2012-01-01 Epub Date: 2012-11-26 DOI: 10.1155/2012/498931

3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation. Identifying an active conformation of a flexible molecule is technically difficult. It has been a bottleneck in the application of the 3D-QSAR method. We have developed a 3D-QSAR software named AutoGPA especially based on an automatic pharmacophore alignment method in order to overcome this problem which has discouraged general medicinal chemists from applying the 3D-QSAR methods to their "real-world" problems. Applications of AutoGPA to three inhibitor-receptor systems have demonstrated that without any prior information about the three-dimensional structure of the bioactive conformations AutoGPA can automatically generate reliable 3D-QSAR models. In this paper, the concept of AutoGPA and the application results will be described.

三维-QSAR 方法已被广泛应用,并被证明在没有生物活性分子与受体之间复合物的可靠晶体结构的情况下非常有用。但与此同时,它也凸显了这种方法的敏感性。传统 3D-QSAR 方法的主要要求是将分子正确地叠加到假定的生物活性构象中。识别柔性分子的活性构象在技术上非常困难。这一直是 3D-QSAR 方法应用的瓶颈。为了克服这个问题,我们开发了一款名为 AutoGPA 的三维-QSAR 软件,该软件特别基于自动药代配准方法,而这个问题阻碍了普通药物化学家将三维-QSAR 方法应用于他们的 "实际 "问题。AutoGPA 在三个抑制剂-受体系统中的应用表明,无需任何有关生物活性构象三维结构的先验信息,AutoGPA 就能自动生成可靠的 3D-QSAR 模型。本文将介绍 AutoGPA 的概念和应用结果。
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引用次数: 0
Syntheses and biological activity of some derivatives of C-9154 antibiotic. C-9154抗生素衍生物的合成及生物活性研究。
Pub Date : 2012-01-01 Epub Date: 2012-08-06 DOI: 10.1155/2012/148235

This research was undertaken to design several new antibiotics, by structurally modifying the C-9154 antibiotic, simultaneously improving its activity and lowering toxicity. This was achieved by synthesizing an analogue to the C-9154 antibiotic and seven derivatives of this analogue. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were fully characterized using infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogue as was anticipated and both were more active than the standard drugs used for comparison. Work is ongoing to establish applications for the compounds as antiplasmodials, antivirals, anticancers/tumours, antitrypanosomiasis, anthelminthic, and as general antibiotics for human, veterinary, and even agricultural use as they had marked effect on both Gram-positive and Gram-negative bacteria and some fungi.

本研究通过对C-9154抗生素进行结构修饰,设计了几种新的抗生素,同时提高了其活性并降低了毒性。这是通过合成C-9154抗生素的类似物和该类似物的七个衍生物来实现的。该方法是通过将高极性羧基转化为酯官能团来显著降低衍生物中合成类似物的极性,从而增加细胞膜的通透性。通过红外、气相色谱-质谱、一维和二维核磁共振实验对化合物进行了表征。化合物的体外生物活性表明,正如预期的那样,衍生物比类似物更有活性,两者都比用于比较的标准药物更有活性。由于这些化合物对革兰氏阳性和革兰氏阴性细菌以及一些真菌都有显著效果,因此正在开展工作,确定这些化合物作为抗疟原虫、抗病毒药物、抗癌/肿瘤、抗锥虫病、驱虫以及人类、兽医甚至农业用途的一般抗生素的应用。
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引用次数: 5
Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile. 5-取代n-甲基吗啡酮-6-酮作为有效阿片类镇痛药的研究进展。
Pub Date : 2012-01-01 Epub Date: 2012-06-17 DOI: 10.1155/2012/208039

One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs.

阿片系统最重要的功能之一是控制疼痛。在三种主要的阿片受体(μ, δ, κ)中,μ (MOR)是药物治疗疼痛的主要靶向类型。阿片类镇痛药,如吗啡、羟考酮和芬太尼,是MOR的激动剂,是治疗中重度疼痛的主要药物。然而,与阿片类药物使用有关的不良反应是严重的,经常导致早期停药和止痛不足。开发更有效和更安全的治疗疼痛的药物仍然是药物研究的一个主要方向。鉴定具有低副作用的新型MOR镇痛药的化学方法包括在关键位置对14-烷氧基- n-甲基吗啡-6- 1进行结构修饰,这对阿片受体的结合、选择性、效价和疗效至关重要。本文介绍了一种具有代表性的策略,以提高阿片类镇痛药的治疗有效性,从吗啡类药物靶向位置5。重点是这一系列配体的化学和生物学研究以及构效关系。我们报道了在5位有甲基和苄基的14-烷氧吗啡酮-6- 1作为强阿片类抗痛觉药物,与吗啡相比,尽管选择性地与MORs相互作用,但其引起不良反应的倾向降低。
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引用次数: 8
Current updates on oxazolidinone and its significance. 恶唑烷酮及其重要性的最新进展。
Pub Date : 2012-01-01 Epub Date: 2012-02-26 DOI: 10.1155/2012/159285

Oxazolidinone is a five-member heterocyclic ring exhibiting potential medicinal properties with preferential antibacterial activity. Scientists reported various synthetic procedures for this heterocyclic structure. Current review articles tried to cover each and every potential aspect of oxazolidinone like synthetic routes, pharmacological mechanism of action, medicinal properties, and current research activities.

恶唑烷酮(Oxazolidinone)是一种五元杂环,具有潜在的药用特性和抗菌活性。科学家们报道了这种杂环结构的各种合成程序。当前的综述文章试图涵盖噁唑烷酮的每一个潜在方面,如合成路线、药理作用机制、药用特性和当前的研究活动。
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引用次数: 0
MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys. MDAN-21:一种含mu激动剂和delta拮抗剂的二价阿片配体及其在恒河猴中的作用。
Pub Date : 2012-01-01 Epub Date: 2012-04-29 DOI: 10.1155/2012/327257

MDAN-21, 7'-{2-[(7-{2-[({(5α, 6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006-0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032-0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain.

mdan - 21,7 '-{2-[(7-{2-[({(5α, 6α)-4,5-环氧-3,14-二羟基-17-甲基吗啡-6-基}-氨基羰基)甲氧基]-乙酰氨基氨基}-纳尔曲多是一种二价阿片配体,含有一种μ -阿片受体激动剂(衍生自氧吗啡酮),通过21个原子的间隔连接到δ -阿片受体拮抗剂(与纳尔曲多相关),据报道在小鼠中具有有效的镇痛作用。耐受性、身体依赖性和条件位置偏好在该物种中不明显。该系列的二价配体(间隔物为19个原子或更大)缺乏耐受性和依赖性,因此提出MDAN-21靶向异构体多δ阿片受体。目前的研究主要集中在它对非人灵长类动物(猕猴)的影响上,这是一种与人类有着生理和行为特征的物种。关于阿片类药物,这个物种通常能更好地预测临床结果。MDAN-21在吗啡依赖猴皮下注射0.006 ~ 0.032 mg/kg的极低剂量范围内替代吗啡。虽然MDAN-21在0.0032-0.032 mg/kg的剂量范围内不能产生可靠的热镇痛,但在相同剂量范围和相同给药途径下,在辣椒素诱导的热异常痛实验中,它是有活性的。结果表明,MDAN-21可能有助于治疗阿片类药物依赖和异常性疼痛。这些数据提供了阿片类药物戒断与致敏性疼痛相关的额外证据。
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引用次数: 26
Aurones: a promising heterocyclic scaffold for the development of potent antileishmanial agents. Aurones:一种有前途的用于开发强效抗利什曼原虫药物的杂环支架。
Pub Date : 2012-01-01 Epub Date: 2012-09-25 DOI: 10.1155/2012/196921

A series of (Z)-2-benzylidenebenzofuran-3-(2H)-ones (aurones) bearing a variety of substituents on rings A and B were synthesized and evaluated for their antiparasitic activity against the intracellular amastigote form of Leishmania infantum and their cytotoxicity against human THP1-differentiated macrophages. In general, aurones bearing no substituents on ring A (compounds 4a-4f) exhibit higher toxicity than aurones with 4,6-dimethoxy substitution (compounds 4g-4l). Among the latter, two aurones possessing a 2'-methoxy or a 2'-methyl group (compounds 4i and 4j) exhibit potent antileishmanial activity (IC50 = 1.3 ± 0.1 μM and IC50 = 1.6 ± 0.2 μM, resp.), comparable to the activity of the reference drug Amphotericin B, whereas they present significantly lower cytotoxicity than Amphotericin B as deduced by the higher selectivity index.

合成了一系列在A环和B环上含有多种取代基的(Z)-2-苄基苯并呋喃-3-(2H)-酮(aurones),并评估了它们对婴儿利什曼原虫胞内无尾虫形式的抗寄生活性和对人thp1分化巨噬细胞的细胞毒性。一般来说,A环上没有取代基的aurones(化合物4a-4f)比4,6-二甲氧基取代的aurones(化合物4g-4l)具有更高的毒性。其中,含有2′-甲氧基或2′-甲基的两个aurones(化合物4i和4j)表现出与对照药物两性霉素B相当的抗利什曼原虫活性(IC50分别为1.3±0.1 μM和1.6±0.2 μM),但从更高的选择性指数推断,它们的细胞毒性明显低于两性霉素B。
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引用次数: 39
期刊
International Journal of Medicinal Chemistry
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