新型非肽类血管紧张素II受体拮抗剂设计合成及其生物活性研究

Ang II受体拮抗剂是作用于肾素-血管紧张素系统(RAS)的抗高血压药，因其抗高血压作用与较老的抗高血压药物作用相同，且更具有选择性，不良反应状况与安慰剂相似,而在高血压治疗中逐渐引起研究者重视，并成为目前增长最快的抗高血压药物。在许多AngII受体拮抗剂中四氮唑结构已成为固定基团，但四氮唑有许多合成及代谢弊端。因此，寻找其他合适的杂环酸性基团来替代四氮唑，在保持较高口服活性的同时克服相应缺陷，具有极其重要的意义。 本项目以四氮唑沙坦类药物为先导化合物，运用生物电子等排原理及拼合原理，根据计算机分子模拟研究结果，对其进行结构修饰和改造，首次将咪唑、氯代咪唑、三氮唑及咪唑啉替代四氮唑，并结合具有较高AngII受体拮抗活性的联苯并咪唑衍生物，设计并合成一系列含咪唑，咪唑啉，氯代咪唑及三氮唑衍生物的Ang II受体拮抗剂。 研究这一系列新型AngII受体拮抗剂的体内、体外抗高血压活性时，发现咪唑啉衍生物展示了与对照药物几乎相当的活性，而咪唑、氯代咪唑和三氮唑衍生物分别表现了较弱或者没有活性，这些研究对今后更进一步设计合成新的Ang II受体拮抗剂具有重要的指导意义，同时也为筛选抗高血压药物奠定良好的基础。 The angiotensin II receptor antagonists act on renin-angiotensin system (RAS), which are as effective as other types of anti-hypertensive drugs. Because even the more specific and comparable to placebo in terms of side effects, Ang II receptor antagonists cause a high attention and become the fastest growing anti-hypertension drugs. Most of such compounds share the biphenyltetrazole unit with the lead Losartan. However, there are many defects in tetrazole synthesis and vivo metabolism. Therefore, we felt quite encouraged to find some proper acidic heterocyclic groups which maintain the same oral bioavailability to replace the tetrazole. In the present paper, we applied the bioisostere and combination principle, in accordance with the results of computer modeling of molecular, to modify the lead structural of terazole in sartan compounds reported. We turned our attention to replace the tetrazole ring with imidazole rings, chloro-imidazole, imidazoline, traizole ring and combinated them with benzimidazoles derivatives which have antagonistic activity for angiotensin II to design and synthesize a series of Ang II receptor antagonists contaning imidazole ring, chloro-imidazole, imidazoline or traizole ring. In addition, activity tests in vivo and in vivo had shown that imidazoline derivatives display almost equivalent activity with the reference drug, but imidazole derivatives, chloro-imidazole, triazole derivatives were weak or non-performance of the hypotensive activity. We believe that the imidazoline derivative type Ang II receptor antagonists can build a foundation for the development of a novel series of anti-hypertensive drugs.

Impact of astaxanthin-enriched algal powder of Haematococcus pluvialis on memory improvement in BALB/c mice

The impact of astaxanthin-enriched algal powder on auxiliary memory improvement was assessed in BALB/c mice pre-supplemented with different dosages of cracked green algal (Haematococcus pluvialis) powder daily for 30 days. The supplemented mice were first tested over 8 days to find a hidden platform by swimming in a Morris water maze. Then, for 5 days, the mice were used to search for a visible platform in a Morris water maze. After that, the mice practised finding a safe place-an insulated platform in a chamber-for 2 days. During these animal experimental periods, similar algal meals containing astaxanthin at 0, 0.26, 1.3 and 6.4 mg/kg body weight were continuously fed to each group of tested mice. Profiles of latency, distance, speed and the direction angle to the platforms as well as the diving frequency in each group were measured and analyzed. The process of mice jumping up onto the insulated platform and diving down to the copper-shuttered bottom with a 36 V electrical charge were also monitored by automatic video recording. The results of the Morris maze experiment showed that middle dosage of H. pluvialis meals (1.3 mg astaxanthin/kg body weight) significantly shortened the latency and distance required for mice to find a hidden platform. However, there was no obvious change in swim velocity in any of the supplemented groups. In contrast, the visible platform test showed a significant increase in latency and swim distance, and a significant decrease in swim speed for all groups of mice orally supplemented with H. pluvialis powder compared to the placebo group (P < 0.05 or P < 0.01). Mice supplemented with the algal meal hesitantly turned around the original hidden platform, in contract to mice supplemented with placebo, who easily forgot the original location and accepted the visible platform as a new safe place. These results illustrate that astaxanthin-enriched H. pluvialis powder has the auxiliary property of memory improvement. The results from the platform diving test showed that the low and middle dosage of H. pluvialis powder, rather that the high dosage, increased the latency and reduced the frequency of diving from the safe insulated platform to the electrically stimulated copper shutter, especially in the low treatment group (P < 0.05). These results indicate that H. pluvialis powder is associated with dose-dependent memory improvement and that a low dosage of algal powder (<= middle treatment group) is really good for improving the memory.

迁移性安慰剂效应的多模态机制 ：从痛觉到情绪的行为、ERP和fMRI研究

Although studies on placebo effect proved the placebo expectation established by pain-alleviating treatment could significantly alleviate later pain perception, or the placebo expectation established by anxiety-reducing treatment could significantly reduce the intensity of induced negative feelings, it is still unclear whether or not the placebo effect can occur in a transferable manner. That is, we still don’t know if the placebo expectation derived from pain-alleviating can significantly reduce later negative emotional arousal or not. Experiment 1: We compared the effect of the verbal expectation (purely verbal induction and without pain-alleviating reinforcement) with the reinforced expectation (building the belief in the placebo’s ataractic efficiency on unpleasant picture processing by secret reduction of the intensity of the pain-evoking stimulus) on the negative emotion. The results showed that the expectation, which was reinforced by actual analgesia, was transferable and could produce significant placebo effect on negative emotional arousal. However, the expectation that was merely induced by verbal instruction did not have such power. Experiment 2 both examined the direct analgesic effect of the placebo on the sensory pain (how strong is the pain stimulus) and emotional pain (how disturbing is the pain stimulus) and the transferable ataractic effect of the placebo on the negative emotion (how disturbing is the emotional picture stimulus), and further proved that the placebo expectation that was established from pain-reducing reinforcement not only induced significant placebo effect on pain, but also significant placebo effect on unpleasant feeling. These results support the viewpoint that the reduction of affective pain based on the conditioning mechanism plays an important role in the placebo analgesia, but can’t explain the transferred placebo effect on visual unpleasantness. Experiment 3 continued to use the paradigm of the reinforced expectation group and recorded the EEG activities, the data showed that the transferable placebo treatment was accompanied with decreased P2 amplitude and increased N2 distributed, and significant differences between the transferable placebo condition and the control condition (i.e., P2 and N2) were observed within the first 150-300 ms, a duration brief enough to rule out the possibility that differences between the two conditions merely reflect a bias “to try to please the investigator. In Experiment 4, we selected the placebo responders in the pre-experiment and let them to go through the formal fMRI scan. The results found that the transferable placebo treatment reduced the negative emotional response, emotion-responsive regions such as the amygdala, insula, anterior cingulate cortex and the thalamus showed an attenuated activation. And in the placebo condition, there was an enhanced activation in the subcollosal gyrus, which may be involved in emotional regulation. In conclusion, the transferable placebo treatment induced the reliable placebo effect on the behavior, EEG activity and bold signal, and we attempted to discuss the pychophysiological mechanism based on the positive expectancy.