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维拉佐酮合成路线图解 总被引:1,自引:0,他引:1
维拉佐酮(vilazodone,1)化学名为1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨甲酰基苯并呋喃-5-基)哌嗪,其盐酸盐的商品名为 Viibryd,是由美国 Trovis Pharmaceuticals LLC 公司开发的一种具有双重作用的选择性 5-羟色胺再摄取抑制剂和5-HTIA受体部分激动剂。2011年1月,美国食品药品管理局(FDA)批准盐酸维拉佐酮片用于治疗成年中重度抑郁症。维拉佐酮抗抑郁作用的机制尚未完全阐明, 目前认为维拉佐酮与5-羟色胺再摄取位点的亲和力高,而与去甲肾上腺素或多巴胺再摄取位点无高亲和力,同时与5-HT1A受体亲和力高。维拉佐酮的临床试验数据表明,其疗效明显优于安慰剂,耐受性好, 不良反应小。 相似文献
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5-HT重摄取抑制/5-HT1A受体拮抗双重作用抗抑郁药是在单胺递质学说的基础上研发的新一代抗抑郁药,此类药物研发的策略主要是通过分子拼合原理,在单一分子中引入2种药效团在体内共同发挥抗抑郁作用.文中对该类药物中几种典型的结构构效关系及生物活性评价结果进行综述,以期为抗抑郁药物的研发提供参考.新型化合物在有效性、安全耐受性及起效时间等方面表现出很多优势,但是目前还没有相关的临床报道数据. 相似文献
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5盐酸维拉唑酮的不良反应5.1临床研究的结果经盐酸维拉唑酮治疗的重度抑郁症(MDD)患者,最常见的不良反应如腹泻、恶心、呕吐和失眠的发生率≥5%,至少是安慰药的2倍。临床试验是在广泛的不同情况下进行的,而且时间长短不一,试验药物所观察到的不良反应发生率无法直接与其他药物比较,也不能反映实际情况。MDD患者与 相似文献
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目的研究安非他酮治疗抑郁症和焦虑症的临床疗效。方法将30例抑郁症患者和20例焦虑症患者分别给予安非他酮治疗,疗程6周。采用汉密顿抑郁量表(HAMD)评定临床疗效。结果治疗30例抑郁症中,痊愈率可达80%;对双相情感障碍抑郁发作更有效,10例中9例痊愈,且无转躁现象,而其他三环抚抑郁药和新型抗抑郁药常诱发躁狂发作。结论安非他酮是治疗抑郁症和焦虑症的有效药物,甚至优于其他新型抗抑郁药物。临床发现新型抗抑郁药如5-HT再摄取抑制剂和SNRI类如文拉法辛等所致恶心、头胀、紧张、嗜睡等副反应较常见,一定程度上影响其临床应用。盐酸安非他酮治疗应用中发现其抗抑郁和抗焦虑作用与上述新型抗抑郁药相似,且不良反应用较少。可作为首选药物。 相似文献
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N-吲哚烷基哌啶类化合物及其类似物的合成和活性研究 总被引:1,自引:0,他引:1
摘 要:目的 以5-羟色胺转运体和5-HT2A受体为靶点,设计合成N-吲哚烷基哌啶类化合物及其类似物,研究它们的体内外生物活性。方法 以苯并五元氮杂化合物为原料,经烷基化反应,再与相应的哌啶或哌嗪类化合物进行缩合制备系列化合物。经5-羟色胺再摄取抑制实验和5-HT2A受体结合实验进行体外筛选,采用小鼠醋酸扭体法和小鼠热板法对其中优选化合物10c、10e进行体内镇痛活性实验;通过阿片受体结合试验和小鼠急性毒性试验,考察目标化合物作为新型非阿片类镇痛剂的潜在开发价值。 结果与结论 共合成了18个未见文献报道的新化合物, 经高分辨质谱及核磁共振氢谱确证结构。体内外药理研究表明:化合物10c和10e具有较强的5-羟色胺再摄取抑制作用,且与5-HT2A受体有较高亲和力;10c、10e在两种镇痛模型上均显示出很强的镇痛活性;与阿片μ、δ、κ受体无明显亲和力;毒性较小,具有作为非阿片类新型镇痛剂的开发价值。 相似文献
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双重作用的多巴胺D2/5-HT2A受体拮抗剂比较药效团分析 总被引:1,自引:0,他引:1
双重作用的多巴胺D2/5-HT2A受体拮抗剂是开发非典型抗精神病药物的有效途径,但最新研究显示, 非典型抗精神病药物将显著增加患者因心律失常及其他心脏疾病而猝死的风险,本文对D2/5-HT2A受体拮抗剂的药效团模型以及可能引起心血管风险的α1A肾上腺素受体拮抗剂和hERG K+通道阻断剂的药效团模型进行比较分析,从药效团模型的角度分析多靶点药物的设计。 相似文献
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目的为寻找新型的5-HT2A受体选择性配体,设计合成了一系列二芳烷基哌啶类化合物的含硫衍生物。方法以2,3-二甲氧基硫酚为原料,经烃化、氧化和水解等反应合成3个N-取代哌啶-4-苯硫醚和砜类化合物,所有目标化合物结构均经元素分析、1HNMR谱、质谱和红外光谱确证,并测定其对5-HT2A,5-HT2C,5-HT6和5-HT7受体及其他一些中枢神经递质受体的体外亲和力。结果3个目标化合物(2a-2c)及5个中间体均为新化合物。体外受体竞争结合试验结果表明2a-2c均有较高的5-HT2A受体选择性。结论此类化合物对5-HT2A受体的选择性较高,值得进一步研究。 相似文献
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P. J. Pauwels Christiane Palmier Delphine S. Dupuis Francis C. Colpaert 《Naunyn-Schmiedeberg's archives of pharmacology》1998,357(5):490-499
Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPγS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg–1 protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was
found that: (i) the maximal [35S]GTPγS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 μM GDP were comparable to that of the native agonist 5-HT; (ii) as compared
to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 μM GDP for
zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53);
and that (iii) maximal [35S]GTPγS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration
from 0.3 to 30 μM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing
the amount of GDP with C6-glial membranes results in an attenuation of both the agonist’s maximal effect and the apparent
potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists.
Received: 28 October 1997 / Accepted: 14 February 1998 相似文献
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嵇汝运 《国外医学(药学分册)》1997,(2)
萘法唑酮萘法唑酮(nefazodone)是改造曲唑酮(tra-zodone)的化学结构而开发的新药,于1994年12月经美国FDA批准用于抑郁症的治疗。萘法唑酮是5-羟色胺能5-HT2受体拮抗剂。5-HT2受体的功能包括抑制5-HT1A受体活力,萘法唑酮对5-HT2受体的拮抗作用便增强了5-HT1A受体的活性,从而表现抗抑郁作用。抑郁症患者的5-HT1A受体的敏感性已经降低,另有一些5-HT1A受体激动剂有抗抑郁作用。萘法唑酮还抑制5-HT与去甲肾上腺素的再摄取,这作用与三环类抗抑郁药相似。萘法… 相似文献
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文拉法辛的药理学与临床应用 总被引:26,自引:6,他引:26
文拉法辛 (venlafaxine)是一种新型抗抑郁药 ,能显著抑制 5 HT和NE在神经突触部位的重摄取 ,微弱抑制DA的重摄取。它与M胆碱受体 ,组胺H1受体 ,肾上腺素α1,α2 ,β受体几乎无亲和力。动物实验和临床研究表明 ,文拉法辛能影响精神及行为 ,有效改善抑郁病人的症状。与三环类抗抑郁药比较起效快 ,不良反应少。本文综述了其药物动力学、药理作用、临床疗效和不良反应等。 相似文献
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抑郁症的发病机制非常复杂,至今尚未完全阐明。大量临床及临床前研究表明,5-羟色胺(5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一。在5-HT神经系统中,除5-羟色胺转运体(SERT)外,有多种5-HT受体亚型与抑郁症有关,尤以5-HT1A及5-HT2A受体与抑郁症关系最为密切。5-HT2A受体在大脑中广泛分布,是调节情绪的重要物质基础,对情绪、感知的调控具有重要作用。5-HT2A受体可以直接或间接调节单胺类递质释放,调节脑中单胺类递质水平,参与抑郁症发病过程。5-HT2A受体拮抗剂可以增强5-羟色胺再摄取抑制剂等抗抑郁药对难治性抑郁症的治疗效果并减少性功能障碍及睡眠障碍等不良反应。目前有不少以5-HT2A受体为靶点的抗抑郁药应用于临床,也有大量化合物处于临床及临床前研究。该文对5-HT2A受体与抑郁症的关系及以5-HT2A受体为靶点的抗抑郁药研究进展进行简要综述,以期为新型抗抑郁药物的研发提供参考。 相似文献
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目的探讨5-HT对大鼠DRG神经元膜GABA-激活电流的调节作用及其机制。方法在新鲜分离的大鼠DRG神经元标本上,以全细胞膜片钳技术记录膜电流,用排管快速换液装置行胞外给药,以胞内透析技术分析信号转导途径。结果给予GABA可使多数受检细胞产生浓度依赖性内向电流(IGABA)。预加5-HT,可使IGABA增加。此效应可被5-HT2受体特异性激动剂α-methyl-5-HT(1×10-6 mol·L-1)所模拟,被5-HT2受体选择性拮抗剂cyproheptadine所阻断。在部分细胞,5-HT本身可引起由5-HT3受体介导的快速内向电流,但并未发现该电流与5-HT对IGABA的增强作用有必然的联系。从GABA激活电流的量效曲线可见,预加5-HT后和对照曲线相比,阈浓度不变、EC50值相近,IGABA最大值增加33.6%。胞内透析GDP-β-S或H-7可取消5-HT增强IGABA的效应,而透析H-9无效。结论5-HT可增强GABA-激活电流,其机制为5-HT2受体激活后通过PKC引起GABAA受体胞内磷酸化所致。 相似文献
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目的考察5-HT2C受体对孵育海马脑片释放分泌型淀粉样前体蛋白(sAPP)的调节。方法应用5-HT\,特异性5-HT2C受体激动剂M-110及其特异性拮抗剂L-107孵育海马脑薄片,及Western blot技术和特异性的针对sAPP氨基末端的单克隆抗体22C11检测释放到孵育液中的sAPP。结果5-HT及特异性5-HT2C受体激动剂M-110在一定的浓度范围内呈浓度依赖性地显著增加sAPP分泌;而特异性5-HT2C受体拮抗剂L-107在一定的浓度范围内则浓度依赖性地显著抑制sAPP分泌。结论5-HT通过激活5-HT2C受体调节孵育海马脑片分泌型淀粉样前体蛋白的释放。 相似文献
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Ildefonso Hervás Núria Bel Andrés G. Fernández José M. Palacios F. Artigas 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(3):315-322
Selective serotonin reuptake inhibitors (SSRIs) reduce the 5-HT release in vivo. This effect is due to the activation of somatodendritic
5-HT1A receptors and it displays a regional pattern comparable to that of selective 5-HT1A agonists, i.e., preferentially in forebrain areas innervated by the dorsal raphe nucleus (DRN). However, despite a comparatively
lower 5-HT1A-mediated inhibition of 5-HT release and a greater density of serotonergic uptake sites in hippocampus, the net elevation
produced by the systemic administration of SSRIs is similar in various forebrain areas, regardless of the origin of serotonergic
fibres. As terminal autoreceptors may also limit the SSRI-induced elevations of 5-HT in the extracellular brain space, we
reasoned that a differential control of 5-HT release by terminal autoreceptors in DRN- and median raphe-innervated areas might
be accountable. To examine this possibility, we have conducted a regional microdialysis study in the DRN, MRN and four forebrain
regions preferentially innervated either by the DRN (frontal cortex, striatum) or the median raphe nucleus (MRN; dorsal and
ventral hippocampus) using freely moving rats. Dialysis probes were perfused with 1 μM of the SSRI citalopram to augment the
endogenous tone on terminal 5-HT autoreceptors. The non-selective 5-HT1 antagonist methiothepin (10 and 100 μM, dissolved in the dialysis fluid) increased extracellular 5-HT in frontal cortex and
dorsal hippocampus in a concentration-dependent manner. The 5-HT1B/1D antagonist GR 127935 was ineffective at 10 μM and tended to reduce 5-HT in dorsal hippocampus at 100 μM. The local infusion
of 100 μM methiothepin significantly elevated the extracellular 5-HT concentration to 142–173% of baseline (mean values of
260 min post-administration) in the DRN, MRN, frontal cortex, striatum and hippocampus (dorsal and ventral). Comparable elevations
were noted in the four forebrain regions examined. As observed in frontal cortex and dorsal hippocampus, the perfusion of
10 μM GR 127935 did not elevate 5-HT in DRN, MRN, striatum or ventral hippocampus. Because the stimulated 5-HT release in
the DRN has been suggested to be under control of 5-HT1B/1D receptors, we examined the possible contribution of these receptor subtypes to the effects of methiothepin in the DRN. The
perfusion of sumatriptan (0.01–10 μM) or GR 127935 (0.01–10 μM) did not significantly modify the 5-HT concentration in dialysates
from the DRN. Thus, the present data suggest that the comparable effects of SSRIs in DRN- and MRN-innervated forebrain regions
are not explained by a preferential attenuation of 5-HT release by terminal 5-HT1B autoreceptors in hippocampus, an area with a low inhibitory influence of somatodendritic 5-HT1A receptors. Methiothepin-sensitive autoreceptors (possibly 5-HT1B) appear to play an important role not only in the projection areas but also with respect to the control of 5-HT release in
the DRN and MRN. In addition, our findings indicate that GR 127935 is not an effective antagonist of the actions of 5-HT at
rat terminal autoreceptors.
Received: 27 February 1998 / Accepted: 12 June 1998 相似文献