用分子模构法建立κ阿片受体激动剂的药效基团

目的：建立非肽类κ阿片受体激动剂的药效基团。方法：从ＭＤＬ ＭＤＤＲ数据库中选出五个高活性非肽类κ阿片受体激动剂，以四氢吡咯环Ｎ原子和乙酰胺基团为叠加点，用分子模构法建立非肽类κ阿片受体激动剂的药效基团。结果：四氢吡咯环、乙酰胺的羰基和与惭酰胺相连的疏水基团为非肽类κ阿片受体激动剂共同结构特征。推测受体Ａｓｐ１３８与甲氢吡咯环的Ｎ原子构成氢键，Ｓｅｒ１８７可能与激动剂的乙酰胺羰基以氢键形式相作用。     

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。     

μ阿片受体及受体—配基相互作用的分子模拟

目的：构建μ阿片受体（μＯＲ）的三维结构模型并研究它与芬太尼衍生物的相互作用。方法：以细菌视紫红南为模板，模拟μＯＲ的三维结构。然后蒋芬太尼衍生物对接到μＯＲ的七个α螺旋束之内，并计算结合能，结果：（１）得以受体－配基作用模型．（２）模型中，基本结合位点可能是Ａｓｐ１７和Ｈｉｓ２９７，Ａｓｐ１４７与配基的正电性能铵基形成强的静电和氢键相互作用，这种作用在Ｈｉｓ２９７和配基的羰基Ｏ原子之间较弱，（３     

非肽类阿片Kappa受体激动剂的研究现状

对非肽类阿片ｋａｐｐａ受体激动剂的研究现状进行了概述，并对其构效关系，类型，作用机制及临床研究近况进行了介绍。提出：深入研究ｋａｐｐａ受体及其激动剂将有助于设计新的，无成瘾性的镇痛剂。     

k阿片受体及其激动剂的药理特性及研究进展

1971年美国斯坦福大学Goldstein等首先应用立体专一性结合实验发现了阿片受体，从而揭开了阿片受体的研究序幕。近20年来，阿片受体的研究成为神经药理学、分子药理学以及整个神经生物学研究中一个极为活跃的领域。阿片受体和阿片样物质受到极大关注的主要原因之一是人们希望找     

高效表达在杆状病毒系统的人μ阿片受体及其药理学特征

AIM: To overexpress human mu-opioid receptor (muOR) with characteristics similar to those of mammalian origin. METHODS: Human muOR with a tag of 6 consecutive histidines at its carboxyl terminus was expressed in recombinant baculovirus infected Sf9 insect cells. Then the pharmacological characterizations of the product were studied by receptor binding assay and cAMP assay. RESULTS: The maximal binding capacity for the [3H]diprenorphine and [3H]ohmefentanyl (Ohm) were 9.1 +/- 0.7 and 6.52 +/- 0.23 nmol/g protein, respectively. The [3H]diprenorphine or [3H] Ohm binding to the receptor expressed in Sf9 cells was strongly inhibited by alpha-selective agonists [D-Ala2, N-methyl-Phe4, glyol5] enkephalin (DAGO), Ohm, and morphine, but neither by the delta-selective agonist [D-Pen2, D-Pen5] enkephalin (DPDPE) nor by the kappa-selective agonist ?trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]? benzacetamide (U50488). NaCl 100 mmol.L-1 and guanosine triphosphate (GTP) 50 mumol.L-1 could reduce mu agonists Ohm and etorphine affinity binding to the expressed muOR. DAGO and Ohm effectively inhibited forskolin-stimulated cAMP accumulation. This agonist-dependent effect was blocked by opioid antagonist naloxone. CONCLUSION: The overexpression of human muOR with a tag of six consecutive histidines at its carboxyl terminus in Sf9 insect cells retained the characteristics of wild-type human muOR.     

阿片受体激动剂吗啡对心脏作用的研究进展

阿片类物质及其受体自从被发现以来。已历经了数百年的时间。人类最早把阿片类药物用于镇痛，吗啡作为阿片类药物首先被分离出来并应用于临床，在一定时期内吗啡对于治疗减轻癌症等引起的疼痛起到了不可替代的作用。随着医学科学技术的发展，吗啡等阿片类受体激动剂已经不仅仅局限在治疗疼痛这一方面，其对于心肌细胞的保护作用的研究近年来尤为突出。在细胞、分子水平上。吗啡可作用于K、6和μ受体，通过PTX-敏感性G蛋白、IP3、PKC及KATP等通路封心肌细胞产生保护作用，促进心肌细胞存活、增殖；抑制心肌细胞凋亡。通过上述机制吗啡在心肌缺血预适应、心肌缺血-再灌注、心肌肥厚以及心力衰竭等方面可发挥重要的保护作用。     

阿片孤儿受体三维结构的比较分子模拟(英文)

目的:建立阿片孤儿受体(ORL1)的三维结构。方法:以蛙视紫红质为模板,用比较分子模拟方法进行序列联配,建立阿片孤儿受体七段跨膜区的结构;通过自己构件的数据库进行搜寻确立膜外环区的构象;对初始模型进行分子力学优化。结果:建立了阿片孤儿受体的三维结构模型;有多个氢键集中区分别存在于跨膜区和膜外环区;保守性的结合口袋位于第三、五、六、七跨膜区;预测可能的结合位点由包含Asp130、Tyr131残基的高度保守区和靠近膜外端的部分可变区组成。结论:模拟膜外环区的方法可用于其他GPCR的分子模拟;所建立的三维结构模型有助于阿片受体的结构功能研究并能为相关实验提供有益信息。     

κ阿片受体介导的降血压作用

目的观察κ阿片受体激动剂U50488H对大鼠血压的影响并探讨其作用机制。方法监测正常大鼠心率(HR)、动脉压(ABP)、左心室内压(LVP)及左室的收缩(+dp/dtm ax)和舒张功能(-dp/dtm ax)等血流动力学指标和尿量的变化;分离正常大鼠腹主动脉,测定血管张力的变化。结果在整体水平,静脉注射U50488H可降低大鼠HR、ABP、LVP及±dp/dtm ax;而且可增加大鼠的尿量。在离体水平,U50488H对大鼠腹主动脉具有明显的剂量依赖性舒张作用;以上效应均可被选择性κ阿片受体阻断剂nor-BNI所阻断。结论激动κ阿片受体可引起降压作用,抑制心肌收缩力、舒张血管和利尿是其降压的主要机制。     

Molecular modeling on kappa opioid receptor and its interaction with nonpeptide kappa opioid agonists 1

目的：研究κ阿片受体及其与非肽类激动剂的作用机制．方法：以细菌视紫红质为模板,模建κ阿片受体七个跨膜区的三维结构;将五个高活性非肽类激动剂对接到螺旋区内,研究作用机制．结果：（１）四氢吡咯环氮原子与Ａｓｐ１３８羧基成氢键;（２）乙酰胺羰基氧与受体Ｓｅｒ１８７间存在氢键作用;（３）与乙酰胺相连的疏水基团处于由Ｖａｌ２３９、Ｖａｌ２３６、Ｐｈｅ２３５、Ｖａｌ２３２、Ｌｅｕ１８６和Ｔｒｐ１８３构成的疏水区域内;（４）激动剂的四氢吡咯环为Ｉｌｅ２９０、Ａｓｐ１３８、Ｉｌｅ１９４、Ｉｌｅ１３５和Ｃｙｓ１３１残基包围．结论：模型将有助于设计新型高效安全的κ阿片受体激动剂．     

Specific kappa opioid receptor agonists

The results of studies on the design of a heterocyclic scaffold for the dynorphin A pharmacophore and on structure-affinity relationships in the MPCB/CCB series are described. The representative ligands provide insights to binding modes of benzomorphan derivatives to the kappa opioid receptor.     

Selective non-peptide kappa opioid receptor agonists

This article provides an overview of the development of selective K-opioid receptor antagonists as potential analgesics and neuroprotective agents. An important milestone in defining the properties of a K-receptor agonist was the discovery of the N-(2-aminocyclo-hexyl)arylacetamide class of selective K-receptor agonist, of which U-50488 was the prototype structure. Most of the subsequently reported classes of K-receptor agonist have their origins in the ethylenediamine amide pharmacophore present in U-50488. These include direct modification of U-50488 itself, structural simplification, (acyclic systems) and modification of the cyclohexane framework (piperidines and piperazines). Such strategies have provided highly potent and selective K-receptor agonists: U-62066 (spiradoline), CI-977 (enadoline), ICI199441, ZT52656 and GR89696. The full clinical picture for K-receptor agonists as analgesics or neuroprotective agents has yet to become available but initial data highlight concerns regarding side-effects of sedation, diuresis and dysphoria. It may be that the emerging picture of K-receptor subtypes will provide new directions in further refining this activity profile.     

Endorphins and food intake: kappa opioid receptor agonists and hyperphagia

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.     

Effect of mu and kappa opioid receptor agonists on rat plasma corticosterone levels

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.     

The opioid receptor independent actions of kappa receptor agonists in the cardiovascular system

It is not well known but the actions of opioid receptor agonist and antagonist drugs have not been well characterized in the heart and cardiovascular system. Under normal physiological conditions, opioid receptors have a limited role in the regulation of the cardiovascular system. Instead the primary focus of opioid receptor research, for many years, relates to the characterization of the actions as analgesics in the central nervous system (CNS). Recently, however a series of studies suggest that in particular the arylacetamide class of kappa (kappa) opioid receptor agonist drugs have significant opioid receptor independent actions on the heart and cardiovascular system. Some of the actions of these molecules may indeed be mediated by activation of peripheral opioid receptors; however, these new studies provide pharmacological evidence to the contrary and show using many different in vitro and in vivo animal models that these 'non-opioid' actions result from direct or opioid receptor-independent actions on cardiac tissue. This article will outline the molecular mechanism(s) that are responsible for the cardiovascular and cardiac actions these arylacetamide kappa opioid receptor agonists and characterize the role that these opioid receptors have in ischaemic arrhythmogenesis. In many instances it would appear that the effects of opioid agonists (and antagonists) in cardiovascular disease models of ischaemia may be mediated by opioid receptor-independent actions of these drugs.     

Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats

Icilin is a cooling agent that precipitates vigorous wet-dog shakes in rats after acute i.p. administration. Recent research has emphasized the peripheral agonist properties (e.g. activation of transient receptor potential channels, TRPM8 and TRPA1) of icilin rather than its unusual and pronounced behavioral effects, often classified as quasi-morphine withdrawal. We tested selective opioid receptor agonists against icilin-induced wet-dog shakes in rats. Shaking was antagonized following s.c. pretreatment with the mu agonists, morphine (1, 2, 3 mg/kg) and buprenorphine (0.10 mg/kg) or the kappa agonists, nalfurafine (0.02, 0.04 mg/kg) and U50,488H (5 mg/kg). Pretreatment with ICI 204,448 (1, 5, 10 mg/kg), the peripherally directed kappa agonist, or the delta agonist, SNC 80 (0.30, 1, 3, 10 mg/kg), had no marked effect on the incidence of shaking. We conclude that (a) icilin can trigger shaking via interactions within the central nervous system and (b) mu and kappa opioid receptors are involved in suppressing this stimulant behavior.