4—甲氧羰基芬太尼4—N—丙酰基衍生物作为阿片受体不可逆配体的合…

本文合成了８个４－甲氧羰基芬太尼４－Ｎ－丙酰基衍生物，其中６个未见文献报道，通过光照甩尾测痛法测定了其镇痛活性，结果表明它们均具有典型的吗啡样镇痛作用。其中目标化合物（２）、（４），（８）的镇痛强度与相当，此外，对化合物（２）、（４）还乾地离体组织试验，结果表明它们均为阿片受体激动剂与阿片受体不可逆配体。     

4-甲氧羰基芬太尼1-位衍生物的合成及生物活性

合成了5个4-甲氧羰基芬太尼1-位衍生物,有4个化合物的分子中带有可与阿片受体发生烷化反应的官能团。镇痛试验结果表明,它们都有典型的吗啡样镇痛活性。离体组织试验结果表明,这些新化合物均作用于阿片受体,其中化合物2,4和5为新型的阿片受体不可逆配体。     

4-甲氧羰基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性

本文报道了4-甲氧羰基芬太尼4-N-丙酰基结构改变衍生物的合成及其镇痛活性。试验结果表明,该类衍生物均具有典型吗啡样作用的性质。多数化合物具有很强的镇痛活性。其中1379,1385和1387的镇痛活性强于先导物4-甲氧羰基芬太尼。     

4-甲氧羰基-4-N-丙酰苯胺基哌啶1位衍生物的合成及其镇痛作用

本文报道了一系列N-[-1(2-苯乙基-4-甲氧羰基-4-哌啶基]-N-丙酰苯胺(4-甲氧羰基芬太尼)哌啶环1位取代衍生物的合成及其镇痛活性;讨论了结构与镇痛活性之间的关系。药理试验结果表明,大部分化合物具有典型的吗啡样镇痛活性,是一类作用极强的麻醉性镇痛剂。特别是哌啶环1位β-苯环被取代乙烯基替代的化合物具有相当或接近子母体化合物的镇痛活性。其代表物1321的镇痛活性(ED_(50)=0.005mg/kg ip,小鼠,热板法)略强于4-甲氧羰基芬太尼(ED_(50)=0.0063 mg/kg)。     

4-甲氧甲基芬太尼类似物的合成及其镇痛作用

本文报道了某些N-[1-(2-苯乙基)-4-甲氧甲基-4-哌啶基]-N-丙酰苯胺(4-甲氧甲基芬太尼)类似物的合成及其镇痛活性。小白鼠热板试验的结果表明,该类化合物有很强的吗啡样镇痛活性,但活性弱于相应的4-甲氧羰基芬太尼类化合物;4-N-酰基上羰基的存在对产生强效镇痛活性有重要作用。     

4-甲氧羰基芬太尼非芳基类似物的合成及镇痛作用

报道了某些4-N-苯基或4-N-苯基与1-β苯基同时被某些非芳香基团替代的4-甲氧羰基芬太尼衍生物的合成及其镇痛活性。结果表明,4-N-苯基和1-β-苯基被某些适宜非芳香基团替代可保持强效镇痛活性。分子中不含苯(或芳)基的化合物4和6的镇痛活性分别是吗啡活性的695倍和818倍。讨论了结构与镇痛活性之间的关系。     

新的高强度高选择性阿片μ受体激动剂［~11C］－羟甲芬太尼的合成

羟甲芬太尼（Ｉ）是一个新的高强度高选择性阿片μ受体激动剂。本文用ｃｉｓ－Ａ－Ｎ－［１－（２－羟基－２－苯乙基）－３－甲基－４－哌啶基］－苯胺（ＩＩ）或ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶基］－苯胺（ＩＩＩ）作为前体合成了［１１Ｃ］－羟甲芬太尼，以便用正电子发射断层扫描（ＰＥＴ）来观察μ受体。通过水解ｃｉｓ－Ａ－羟甲芬太尼（Ｉ）和ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶］－Ｎ－苯基丙酰胺（ｃｉｓ－ＩＶ）的４－Ｎ－丙酰基分别获得ＩＩ和ＩＩＩ。溴乙烷的格氏试剂与回旋加速器产生的［１１Ｃ］－二氧化碳反应后继而直接加入邻苯二甲酸二酰氯和２，６－二叔丁基吡啶生成同位素标记中间体［１１Ｃ］－丙酰氯。［１１Ｃ］－丙酰氯与ＯＨ－前体（ＩＩ）反应后再经ＨＰＬＣ分离纯化直接得［１１Ｃ］－羟甲芬太尼；［１１Ｃ］－丙酰氯与酮－前体（ＩＩＩ）反应后，再用硼氢化钠甲醇溶液处理，然后进行ＨＰＬＣ分离纯化得［１１Ｃ］－羟甲芬太尼。两种方法均可获得ｌｌ．１～１４．８ＧＢｑ／μｍｏｌ的特异性放射化学纯［１１Ｃ］－羟甲芬太尼。总共耗时为４０～５０ｍｉｎ（ＥＯＢ）。     

N－（4－甲氧羰基－4－邻苯二甲酰亚氨基丁酰基）－N－取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道ｌｌ个预期有血管紧张素转化酶抑制活性的Ｎ－（４－甲氧羰基－４－邻苯二甲酰亚氨基丁酰基）－Ａ－取代甘氨酸（ＶＩＩ１－９）、脯氨酸（ＶＩｌ１０）和焦谷氨酸（ＶＩｌ１１）的合成和鉴定。所有上述化合物以及与ＶＩＩ１－９相应的叔丁酯（ＶＩ１～９）均未见文献报道。药理初试结果显示，化合物ＶＩＩ８，ＶＩＩ９和ＶＩｌ１０均有明显降压活性。     

μ阿片受体及其与羧甲芬太尼相互作用的分子模拟

建立μ阿片受体的结构模型，并结合模型研究羧甲芬太尼对该受体的作用机制。以细菌视紫红质的三维结构为模板，在计算机上建立μ阿片受体模型，然后将羟甲芬太尼对接到假想的受体结合部位。得到了良好的配体－受体相互作用模型，发现残基Ａｓｐ１４７与Ｈｉｓ３１９为可能的结合位点。     

Benzimidazole, Benzoxazole and Benzothiazole Derivatives as 5HT2B Receptor Ligands. Synthesis and Preliminary Pharmacological Evaluation

2-Phenethylbenzimidazole, 2-phenethylbenzoxazole and 2-phenethylbenzothiazole derivatives were synthesized to explore the structural features of the serotonin 5-HT_2B receptor antagonists. Those molecules were designed to recognize the 5-HT_2B receptor and to discriminate it from the 5-HT_2A and 5-HT_2C subtypes. All compounds were characterized by binding affinity determination for 5-HT_2A and 5-HT_2C subtypes and antagonistic activity for 5-HT_2B receptor in rat stomach fundus. None of the new compounds showed affinity for 5-HT_2A and 5-HT_2C subtypes, but some of them displayed antagonistic activity in rat stomach fundus at micromolar concentrations.     

具有偏向性的大麻素受体配体研究进展

大麻素受体是多种疾病的潜在治疗靶标,属于G蛋白偶联受体（GPCR）的A家族,主要包括大麻素Ⅰ型受体（CB₁）和大麻素Ⅱ型受体（CB₂）,分布在体内不同部位。现有研究多集中于2种亚型受体的选择性而非具体信号通路的选择性,但已有研究显示信号通路的选择性与成瘾性密切相关。受体激活后,CB₁和CB₂与下游每个信号传导途径的作用程度不同,该现象称为偏向性激动。GPCR与配体结合时的构象是多样化的,偏向性激动剂选择性地稳定一组受体构象,特定地激活下游信号传导途径,从而降低不良反应。综述大麻素受体的结构特征、偏向性信号以及偏向性配体的研究进展,以期为相关研究提供参考。     

Opiate receptor in praying mantis: Effect of morphine and naloxone

A praying mantis displays a “frightening reaction” called deimatic reaction (DR), any time that it is faced with a patterned visual stimulus that represents a potential damage for the insect. Results of the present paper show that the DR could be also elicited by an actual noxious (an electrical shock) and that this response is similar to that elicited by a potential nociceptive stimulus (a patterned visual stimulus). The DR elicited by the electric shock was used as a model for studying the analgesic effect of opiates. The mantis was placed in an apparatus that allowed us to give the insect an electrical shock and to measure the strength of its DR. During a first session the voltage threshold necessary to induce a full DR was determined, and then, the insect was injected with a certain solution. The voltage threshold was tested one, two and four hours after injection. Mantises that were injected with only distilled water showed no changes in their voltage threshold during the three tests. Injections of 300, 350 and 400 μg/g of morphine-HCl increased the voltage threshold in both a time-dependent and a dose related manner. A dose of 350 μg/g of morphine-HCl produced 50% of response inhibition after two hours of injections and is referred to as the median antinoxious dose (AD50). Sixteen μg/g of naloxone given in conjunction with an AD50 of morphine, partially blocked the effect of morphine during the first hour and fully blocked it during the second hour. Thirty-two μg/g of naloxone fully blocked the morphine effect during the first and the second hour. However, more than 48 μg/g of naloxone alone also increased the voltage threshold in insects, similar to those described for vertebrates.     

Synthesis and in vitro Evaluation of Novel Indole-Based Sigma Receptors Ligands

To investigate the molecular features involved in sigma (σ) receptors binding, a series of compounds based on indole scaffolds were synthesized and their chemical structures were confirmed by (1) H-NMR, IR, and elemental analysis. Their affinity toward σ(1) and σ(2) receptor subtypes was evaluated. 1-{[4-(2-phenylethyl)piperazin-1-yl]methyl}-3-methyl-1H-indole 3b had a high affinity to σ(1) receptors, while three compounds, 1-{3-[4-(substitutedphenyl)piperazin-1-yl]propyl}-1H-indole derivatives 4a-c had shown high affinity and selectivity for σ(2) receptors. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7), breast (MCF7), and colon (HCT-116) cancer cell lines. Compound 1c (3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]methyl}-1H-indole) showed significant cell growth inhibitory activity on the selected cancer cell lines.     

Improved Radioreceptor Assay of Opiate Narcotics in Human Serum: Application to Fentanyl and Morphine Metabolism

A recently developed radioreceptor assay (RRA) (1) that employs ³H-naloxone and rat brain membrane homogenates was improved two ways. First, the brain membranes were preincubated in the presence of sodium ions, and second, manganase-II ions were added to the sample incubations. These changes enhanced the assay sensitivity and reproducibility with stored membrane preparations and reduced the effects of serum constituents (Na⁺) on ligand–receptor binding. Patient sera were assayed by radioimmunoassay (RIA) and RRA after fentanyl administration and by high-performance liquid chromatography (HPLC) and RRA after morphine administration. The results with both fentanyl assays were comparable, and no fentanyl metabolites were detectable by RRA after HPLC of serum extracts. In contrast, preliminary results with the HPLC-RRA procedure suggest the presence of an active morphine metabolite of unknown structure in sera obtained from patients on morphine therapy.     

Synthesis and Biological Evaluation of New Quinoxaline Derivatives of ICF01012 as Melanoma-Targeting Probes

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