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1.
参照文献方法合成了18个2,4-二氨基-5-甲基-6-(取代苯胺基)甲基吡啶[2,3-d]并嘧啶化合物(Ⅳ),用Hansch方法研究了它们对L1210细胞株抑制作用的定量构效关系,其结果表明:苯环对位取代基不利于抑制作用,增大5'-取代基的体积同时增加间位(3'和5')取代基团的疏水性可提高抑制作用。 相似文献
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Effects of N-methyl berbamine on delayed outward potassium current in isolated rat hepatocytes 总被引:2,自引:0,他引:2
目的:研究N甲基小檗胺(NMB)对大鼠肝细胞外向钾电流的影响.方法:应用膜片箝技术和全细胞记录方法,箝制电位-50mV,指令电位+30至+140mV,持续时间900ms.结果:NMB以浓度依赖方式降低外向钾电流.电流幅值在20,50,400nmol·L-1和50μmol·L-1时分别从44±10(n=4),25±18(n=4),58±21(n=5),46±13(n=6)nA降到36±04(P>005),21±16(P>005),37±16(P<005),23±13(P<001)nA.抑制率分别为10%,15%,37%,51%.结论:NMB是一种钾通道阻断剂. 相似文献
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4,5-二氢-6-[(苯乙酰基-哌嗪基)苯基]-5-甲基-3(2H)-哒嗪酮对血小板聚集,花生四烯酸代谢及cAMP含量的影响 总被引:1,自引:0,他引:1
4,5-二氢-6-[(苯乙酰基-哌嗪基)苯基]-5-甲基-3(2H)-达嗪酮(SMD。)0.1一2.5pmol·L能使血小板激活因子(PAn及血栓素A,类似物U46619诱导的兔血小板聚集剂量一效应曲线不移且最大反应降低。其pD2分别为6.0±s0.4及6.1±s0.3SMⅡ4还能抑制ADL花生四烯酸(AA)及U46619诱导的人血小板聚集,其IC(50)分别是12,13及1.6μmol.L.用放射性薄层层折及放射免疫测定法分别检测血小板AA代谢产物及cAMP含量表明,SMⅡ4对血小板AA代谢没有显著影响,但能剂量依赖性地升高血小板内cAMP含量,PAFμmol·L不能改变此作用 相似文献
4.
利用3D-QSAR中的CoMFA方法研究了1-环丙基-5-取代-7-(4-甲基哌嗪基)-6,8-二氟-1,4-二氢-4-氧-3-喹啉羧酸定量构效关系。研究表明,从PLS分析的rcv,r值看,模型有效强的预测能力;从立体与静电作用分数比可看出,5位取代基对活性的影响立体效应起主要作用,但静电效应亦十分重要。依据CoMFA系数图设计了一些新化合物,预测结果表明,以5位氨基对抑制革兰氏阳性、阴性菌的活性为最高,与近几年实验研究的结果一致. 相似文献
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2,4-二氨基-5-甲基-6-(取代苯氨基)甲基-吡啶[2,3-d]并嘧啶脂水分配系数的测定 总被引:1,自引:0,他引:1
应用高效液相色谱法测定了15个2,4-二氨基-5-甲基-6-(取代苯氨基)甲基-吡啶[2,3-d]并嘧啶类化合物的保留值,由此推算了它们的脂水分配系数(正辛醇/水).所用固定相为SpherisorbC18(34/118)10μ4.6mm×200mm反向柱,流动相为甲醇-水(57∶43,pH=7.4).所得脂水分配系数(对数值)与用取代基π值计算的数值相差较大 相似文献
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4,5—二氢—6—[(苯乙酰基—哌嗪基)苯基]—5—甲基—3(2H)—哒… 总被引:2,自引:0,他引:2
4,5-二氢-6-[(苯乙酰基-哌嗪基)苯基]-5-甲基-3(2H)-达嗪酮(SMⅡ4)0.1-2.5μmol.L^-^1能使血小板激活因子(PAF)及血栓素A2类似物U46619诱导的兔血小板聚集剂量一效应曲线左移且最大反应降低。其pD2分别为6.0±s0.4及6.1±s0.3.SMⅡ4还能抑制ADP,花生四烯酸(AA)及U46619诱导的人血小板聚集,其IC50分别是1.2,1.3及1.6.. 相似文献
8.
建立了大鼠血浆中4-[4″-(2″,2″,6″,6″-四甲基哌啶氮氧自由基)氨基]-4'-去甲表鬼臼毒素(GP-7)浓度的HPLC测定方法。用ODS柱分离,甲醇-水-冰醋酸(59:41:0.6)为流动相,检测波长285nm。血浆甲乙醚-二氯甲烷混合液萃取,45℃水浴蒸干,残渣用流动相溶解进样,内标法定量;血药浓度在2~200μg·ml-1范围内呈线性关系,r=0.9997,血浆最低检测浓度0.2μg·ml-1,方法回收率94%~100%,日内、日间RSD2.29%~7.70%。大鼠ivGP-710,20,30mg·kg-1,药代动力学过程符合二室开放模型,消除半衰期为39.8±10.8min。 相似文献
9.
本文利用CNDO/2研究了1-取代-7-〔(3-(乙胺基甲基)-1-吡咯烷基〕-6,8-二氟-1,4-二氢-4-氧喹啉-3-羧酸N1位不同取代基的药效构象,首次报道了以第四最低空轨道能(FUMO),超离域度、前沿电子密度等指标与N1位取代基的立体摩尔长度、最小最大宽度等结合的N1位定量构效关系,稍优于文献用经验参数UNSAT的结果,研究表明N1位的活性不仅与立体摩尔长度有关,还与电性效应有关,支持了Domagala以不饱和度参数(UNSAT)所得的结论,但UNSAT的意义不十分明确,本研究的量化指标意义很清楚。 相似文献
10.
石杉碱甲(1)是从中草药千层塔中分离的新型石松类生物碱。药理试验表明它是一个可逆性的强效乙酰胆碱酯酶抑制剂。初步临床试验证实它对记忆衰退、重症肌无力和多发梗死痴呆症具有明显的疗效,有可能成为新一代治疗老年痴呆药物。基于计算机分子模拟研究,石杉碱甲分子中的5-氨甲基-2(1H)-吡啶酮(2)结构可能是其药效部分,因此设计并合成了5-取代氨甲基-2(1H)-吡啶酮类似物(5).(8),(13)和5-取代氨基-5,6,7,8-四氢喹诺酮类似物(16).(17).生物试验表明,这些石杉碱甲简化结构类似物几无抗乙酰胆碱酯酶活性。 相似文献
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The effects of three amphetamine analogs were assessed in pigeons key pecking under a multiple 3-min fixed-interval (FI), 30 response fixed-ratio (FR) schedule of food presentation. At doses between 0.1 and 10.0 mg/kg, (±) 3,4-methylenedioxyamphetamine (MDA), (±) 3,4-methylenedioxymethamphetamine (MDMA), and (±)-N-ethyl-3,4-methylenedioxyamphetamine (MDE) either had no effect or decreased response rates in both components of the multiple schedule in a dose-dependent manner. MDA was at least 1 log unit more potent than the other two compounds. Metergoline (0.1–1.0 mg/kg), a serotonin (5-HT) antagonist with comparable affinity for the 5-HT1 and 5-HT2 receptor subtypes, blocked the rate-decreasing effects of 3.0 mg/kg MDA in both components of the multiple schedule, but did not affect the MDMA dose-response curve. The 5-HT2 receptor antagonist ketanserin (0.1–3.0 mg/kg) also restored FI and FR responding that was decreased by 3.0 mg/kg MDA, but had no effect on responding suppressed by MDMA. The noradrenergic alpha-1 antagonist prazosin (0.3–3.0 mg/kg) blocked the behavioral effects of 3.0 mg/kg MDMA at doses that did not attenuate MDA's rate-decreasing effects. These results indicate that although MDA and MDMA are structurally similar and have similar behavioral effects, their actions appear to be mediated through different neurotransmitter systems. 相似文献
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槲皮素(Que)ig 200mg·kg~(-1),qd×14d可显著降低大鼠心肌和脑钠钾腺苷三磷酸酶(Ⅰ)的活力及心肌钙镁腺苷三磷酸酶(Ⅱ)的活力;槲皮素100mg·kg~(-1)降低心肌Ⅰ的活力,但对脑Ⅰ无明显影响。实验结果提示,大鼠心肌Ⅰ对Que的反应较脑Ⅰ敏感;槲皮素也能显著抑制心肌Ⅱ的活力。 相似文献
13.
《Expert opinion on emerging drugs》2013,18(2):255-271
Background: According to the ‘amyloid cascade hypothesis’ of Alzheimer's disease (AD), abnormal processing of beta-amyloid precursor protein (βAPP) into toxic amyloid beta (Aβ)-peptides is central to the etiopathology of this uniquely human brain disorder. Objective: To review current AD drugs, pharmacological approaches and strategies aimed at modulating Aβ-peptide generation and/or aggregation in the treatment of AD. Methods: Data searches at various websites: Alzheimer Research Forum; individual drug company databases; Medline; Pharmaprojects database; unpublished research; inter-University research communications. Results/conclusion: Considerable research effort has focused on secretase-mediated mechanisms of βAPP processing, and the latest pharmacological strategies have used selective Aβ-peptide-lowering agents (SALA) to provide therapeutic benefit against Aβ-initiated neurodegenerative pathology. Currently, dedicated anticholinesterase, glutamatergic agonist and Aβ-peptide immunization have had little impact in the clinical treatment of AD. One unexpected benefit of statins (HMG-CoA inhibitors), besides their cholesterol lowering abilities, has been their ancillary effects in potentiating the enzymatic mechanisms that generate Aβ-peptides. The long-term benefits or complications of statin-based therapies for use in the clinical management of AD are not known. 相似文献
14.
Richard C. Reichman Nizar Tejani John L. Lambert Joanne Strussenberg William Bonnez Benjamin Blumberg Leon Epstein Raphael Dolin 《Antiviral research》1993,20(4):267-277
Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy (P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time (P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance. 相似文献
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《Expert opinion on therapeutic patents》2013,23(11):1531-1551
Poly(ADP-ribose) polymerase-1 (PARP-1), the most prominent member of the PARP family, is a DNA-binding protein that is activated by nicks in DNA occurring during inflammation, ischaemia, neurodegeneration or cancer therapy. Activated PARP-1 consumes NAD+ that is cleaved into nicotinamide and ADP-ribose and polymerises the latter onto nuclear acceptor proteins. This highly energy consuming process is pivotal for the maintenance of genomic stability although over-activation can culminate in cell dysfunction and necrosis. Therefore, PARP-1 is regarded as a promising target for the development of drugs useful in various forms of inflammation, ischaemia–reperfusion injury and as an adjunct in cancer therapy. This review summarises the structural classes of known PARP-1 inhibitors, with a focus on new inhibitors published for this target, between 2002 and July 2004. The chemistry and biological data disclosed in these patent applications are discussed in light of new structural knowledge of the catalytic domain of the PARP family and recent work with potent inhibitors demonstrating the effects of PARP inhibition in various animal disease models. 相似文献
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D. K. Walker S. J. Bowers R. J. Mitchell M. J. Potchoiba C. M. Schroeder H. F. Small 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(10):1330-1339
1.?Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue.2.?Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites.3.?Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats.4.?Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats. 相似文献
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Convection-enhanced delivery (CED) of GDNF and NTN was employed to determine the tissue clearance of these factors from the rat striatum and the response of the dopaminergic system to a single infusion. Two doses of GDNF (15 and 3 μg) and NTN (10 μg and 2 μg) were infused into the rat striatum. Animals were euthanized 3, 7, 14, 21, and 28 days post-infusion. Brains were processed for ELISA, HPLC, and immunohistochemistry (IHC). Both doses of the infused GDNF resulted in a sharp increase in striatal GDNF levels followed by a rapid decrease between day 3 and 7. Interestingly, IHC revealed GDNF in the septum and the base of the brain 14 days after GDNF administration. Dopamine (DA) turnover was significantly increased in a dose-dependent manner for more than 7 days after a single GDNF infusion. NTN persisted in the brain for at least two weeks longer than GDNF. It also had more persistent effects on DA turnover, probably due to its precipitation in the brain at neutral pH after infusion. Our data suggest that daily or continuous dosing may not be necessary for delivering growth factors into the CNS. 相似文献
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A physiologically based model of human chromium kinetics has been developed, based on an existing physiologically based model of human body and bone growth (O'Flaherty, 1993, Toxicol. Appl. Pharmacol. 118, 16-29; 1995a, Toxicol. Appl. Pharmacol. 131, 297-308; 2000, Toxicol. Sci. 55, 171-18) and an existing physiologically based model of chromium kinetics in rats (O'Flaherty, 1996, Toxicol. Appl. Pharmacol. 138, 54-64). Key features of the adapted model, specific to chromium, include differential absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and concentration-dependent urinary clearance consistent with parallel renal processes that conserve chromium efficiently at ambient exposure levels. The model does not include a physiologic lung compartment, but it can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions generally containing up to 10 mg/day of soluble inorganic salts of either Cr(III) (chromic chloride, CrCl(3)) or Cr(VI) (potassium dichromate, K(2)Cr(2)O(7)) (Finley et al., 1997, Toxicol. Appl. Pharmacol. 142, 151-159; Kerger et al., 1996, Toxicol. Appl. Pharmacol. 141, 145-158; Paustenbach et al., 1996, J. Toxicol. Environ. Health 49, 453-461). In one of the studies, in which the chromium was ingested in orange juice, urinary clearance was observed to be more rapid than when inorganic chromium was ingested. Chromium kinetics were shown not to be dependent on the oxidation state of the administered chromium except in respect to the amount absorbed at these ambient and moderate-to-high exposures. The fraction absorbed from administered Cr(VI) compounds was highly variable and was presumably strongly dependent on the degree of reduction in the gastrointestinal tract, that is, on the amount and nature of the stomach contents at the time of Cr(VI) ingestion. The physiologically based model is applicable to both single-dose oral studies and chronic oral exposure, in that it adequately reproduced the time dependence of blood plasma concentrations and rates of urinary chromium excretion in one of the subjects who, in a separate experiment, ingested daily 4 mg of an inorganic Cr(VI) salt in 5 subdivided doses of 0.8 mg each for a total of 17 days. The high degree of variability of fractional absorption of Cr(VI) from the gastrointestinal tract leads to uncertainty in the assignment of a meaningful value to this parameter as applied to single Cr(VI) doses. To model chronic oral chromium exposure at ambient or moderately above-ambient levels, the physiologically based model in its present form should be usable with urinary clearance set to a constant value of 1-2 liters/day and the gastrointestinal absorption rate constants set at 0.25/day for Cr(III) and 2.5/day for Cr(VI). The model code is given in full in the Appendix. 相似文献
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Objective: Since increasing acute pancreatitis (AP) severity is significantly associated with mortality, accurate and rapid determination of severity is crucial for effective clinical management. This study investigated the value of the revised Atlanta classification (RAC) and the determinant-based classification (DBC) systems in stratifying severity of acute pancreatitis.Methods: This retrospective observational cohort study included 480 AP patients. Patient demographics and clinical characteristics were recorded. The primary outcome was mortality, and secondary outcomes were admission to intensive care unit (ICU), duration of ICU stay, and duration of hospital stay.Results: Based on the RAC classification, there were 295 patients with mild AP (MAP), 146 patients with moderate-to-severe AP (MSAP), and 39 patients with severe AP (SAP). Based on the DBC classification, there were 389 patients with MAP, 41 patients with MSAP, 32 patients with SAP, and 18 patients with critical AP (CAP). ROC curve analysis showed that the DBC system had a significantly higher accuracy at predicting organ failure compared to the RAC system (p?.001). Multivariate regression analysis showed that age and ICU stay were independent risk factors of mortality.Conclusion: The DBC system had a higher accuracy at predicting organ failure. Age and ICU stay were significantly associated with risk of death in AP patients. A classification of CAP by the DBC system should warrant close attention, and rapid implementation of effective measures to reduce mortality. 相似文献