从组胺H3受体的配体开发新药的展望

近年通过克隆技术鉴定了组胺H3和H4亚型受体。H3受体是突触前受体，其功能为调节组胺的生物合成与从末梢释放。在其他神经元也有H5受体的存在，因而还能调节其他若干神经递质的释放。已经发现了一些H3受体的激动剂与拮抗剂，实验研究表明这些激动剂与拮抗剂有广泛的生物作用。迄今尚未有这类化合物经批准在临床应用，但从其功用来日可能开发出一些有效药物。     

NMDA受体甘氨酸拮抗剂研究的新进展

本文综述作了于甘氨酸调节部位的非竞争性Ｎ－甲基－Ｄ－天冬氨酸受体结抗剂研究的最新进展；分析阐述了喹啉类衍生物、喹喔啉类衍生物、吲哚类衍生物以及吡咯酮化合物的结果特征与ＮＭＤＡ受体Ｇｌｙ调节部位拮抗作用之间的关系。     

配体诱导受体酪氨酸激酶活化的结构基础研究进展

受体酪氨酸激酶(RTK)家族是一类具有内源性蛋白酪氨酸激酶(PTK)活性的单次跨膜膜受体。它们在调控与细胞增殖、分化等相关的信号转导通路中起关键作用。它与配体结合后引起二聚化或结构重排而使胞内区的酪氨酸(Tyr)被自磷酸化、Try的自磷酸化一方面可以激活胞内PTK区的活性，另一方面可以为下游的信号蛋白提供结合位点从而完成活化过程。本文对RTK家族成员的晶体结构及其活性调节机制的研究进行了综述，阐述了由配体诱导RTK活化的结构基础，并简要讨论了RTK抑制剂可能的作用靶点。     

人血小板上的ADP受体

５＇一二磷酸腺苷（ＡＤＰ）引起人的血小板聚集，但血小板与ＡＤＰ的反应方式尚不明确。在激活血小板过程中，细胞内ＣＡ＾２＋浓度的增加起重要作用。ＡＤＰ是怎样引起Ｃａ＾２＋浓度增加，以及它用什么样的信号传导机制，尚不清楚。也不清楚ＡＤＰ发挥作用是与血小板上ＡＤＰ的一个受体还是多个受体的相互作用结果。本文叙述了一些有关资料，得出了一些人的血小板上ＡＤＰ受体的数量与性质的试验性结论。     

阿片受体及其配体

阿片类药物的镇痛与成瘾机制近年来的研究进展迅速。目前 ,人们已发现 μ、δ、κ、ＯＲＬ１、ε、σ、λ、ι和ζ９种阿片受体 ,且每种受体均有不同的亚型。在这９种受体中 ,研究最多的是 μ、δ、κ、ＯＲＬ１ ,本文根据国内外研究成果及最新研究进展 ,从分子生物学与分子药理学的角度就 μ、δ、κ、ＯＲＬ１阿片受体的情况做一简单介绍。１ μ-受体１９９３年 ,Ｗａｎｇ［１］等报道成功克隆了 μ-受体 ,到２０００年已发现７种 μ-受体亚型 ［２］ ,它们是ＭＯＲ -１的１０个外显子多种组合形成的。其组成结构分别为ＭＯＲ -１(外显子…     

选择性作用于肾上腺素受体的药物

简述肾上腺素受体的分型、功能及两种新的肾上腺素受体亚型。阐述选择性作用于肾上腺素受体药物的开发及其临床应用情况，详细介绍了几种新型的选择性肾上腺素受体药物。     

速激肽受体拮抗剂研究近况

速激肽受体拮抗剂分为ＮＫ－１、ＮＫ－２／ＮＫ－和ＮＫ／３受体拮抗剂四类，对于前三类已开发了相应的高选择性高效非肽类或环肽类拮抗剂。这些拮抗剂在支气管哮喘、炎症、疼痛、咳嗽和呕吐等的防治文献已显示一定的应用前景。     

甾体药物化学的新进展——甾体受体的研究近况

从近代分子水平研究的基础上，对甾体受体的基本结构与键合区域，甾体受体拮抗剂与激动剂及其作用机制等甾体药物化学方面的进展进行了综述，并介绍了开环甾体维生素Ｄ的结构与活性，以及用于某些肿瘤检测，能与雌激素受体显影剂。     

抑郁症受体机制研究进展

以往研究证实,抑郁症与单胺类受体有关,现阶段又发现了多种受体参与了抑郁症的病理生理过程。该文综述了谷氨酸受体、促肾上腺皮质激素释放激素受体、神经激肽受体、糖皮质激素受体在抑郁症发病机制中所起作用的研究进展。     

抑郁症相关受体作用机制的研究进展

抑郁症是一种病因很复杂的疾病,其发病机制与受体有着密切的关系。本文简要介绍了几种与抑郁症相关的受体,阐述了其生理功能及在抑郁症发病机制中的作用。     

N-甲基-D-天冬氨酸型谷氨酸受体的调节与氰化物中枢毒作用

氰化物可通过间接与直接两条途径激活(N-甲基-D-天冬氨酸型)NMDA受体，首先氰化物引起的能量障碍能通过促使细胞外谷氨酸(Glu)浓度增高和细胞内Ca^2 稳态失调，间接地激活NMDA受体，其次氰化物可能作为NMDA受体直接的调节剂，通过调节NMDA受体中NR1或NR2亚型等半胱氨酸残基的氧化还原位点，提高NMDA受体的活性，随着间接和直接NMDA受体的激活，产生一系列由NMDA受体介导的中枢毒作用，最终导致神经元细胞损伤、凋亡及死亡。由此认为NMDA受体的激活在氰化物诱导的神经损伤机制中可能起关键的作用。     

Activation of the NMDA/glutamate receptor complex antagonizes the NMDA antagonist-induced antidepressant-like effects in the forced swim test

The antidepressant activity of NMDA receptor antagonists has been demonstrated, and their mechanism of action was based on the assumption of their selectivity for the NMDA receptor only. However, no direct evidence for the NMDA receptor role in this activity was demonstrated. Now, in order to prove the NMDA pathway of antidepressant-like action of the NMDA antagonists in the mouse forced swim test (FST) we examined if antidepressant activity of NMDA receptor antagonists is mediated by NMDA receptors and whether the activation of different modulatory sites of the NMDA receptor complex influence the action of the antagonists of different sites of NMDA receptor. In our study, we used two NMDA ligands: competitive NMDA glutamate site antagonist CGP 37849, and glycineB antagonist L-701,324; both at doses found to be effective in the FST. The antidepressant-like activity of the compounds was abolished by the N-methyl-D-aspartic acid (NMDA) or by D-serine co-treatment. Ligands at the doses active in the FST did not alter locomotor activity. The present study indicates the major role of the NMDA/glutamate pathway in the antidepressant-like activity of NMDA antagonists in the mouse FST.     

Rat brain N-methyl-D-aspartate receptors require multiple molecules of agonist for activation

N-Methyl-D-aspartate (NMDA) receptors mediate important physiological and pathological processes, including long term potentiation and neuronal excitotoxicity. Elucidation of mechanisms underlying NMDA receptor functioning will promote understanding of the molecular bases of NMDA receptor-mediated processes. The localization of the phencyclidine (PCP) receptor within the ionophore of the NMDA receptor-gated ion channel permits the binding of PCP receptor ligands to serve as a functional marker of channel activation. We have previously demonstrated that the highly selective PCP receptor ligand [3H]MK-801 displays multiexponential kinetics of association, indicating that the NMDA receptor functions according to a multistate model. Using the fast component of [3H]MK-801 binding to PCP receptors as a marker for activated NMDA channels, we demonstrate here a Hill coefficient of 2 for activation of NMDA channels by L-glutamate. A multistate model of NMDA receptor functioning analogous to the model known to account for the functioning of nicotinic cholinergic and gamma-aminobutyric acidA receptors fits well to our experimental data, supporting the concept that the NMDA receptor is properly classified in the Class 1 superfamily of ligand-gated channels.     

Effects of protopanaxatriol-ginsenoside metabolites on rat N-methyl-d-aspartic Acid receptor-mediated ion currents

Ginsenosides are low molecular weight glycosides found in ginseng that exhibit neuroprotective effects through inhibition of N-methyl-D-aspartic acid (NMDA) receptor channel activity. Ginsenosides, like other natural compounds, are metabolized by gastric juices and intestinal microorganisms to produce ginsenoside metabolites. However, little is known about how ginsenoside metabolites regulate NMDA receptor channel activity. In the present study, we investigated the effects of ginsenoside metabolites, such as compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT), on oocytes that heterologously express the rat NMDA receptor. NMDA receptor-mediated ion current (I(NMDA)) was measured using the 2-electrode voltage clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, PPT, but not CK or PPD, reversibly inhibited I(NMDA) in a concentration-dependent manner. The IC(50) for PPT on I(NMDA) was 48.1±4.6 μM, was non-competitive with NMDA, and was independent of the membrane holding potential. These results demonstrate the possibility that PPT interacts with the NMDA receptor, although not at the NMDA binding site, and that the inhibitory effects of PPT on I(NMDA) could be related to ginseng-mediated neuroprotection.     

选择性NMDA受体NR2B亚单位拮抗剂与神经元保护作用

多种神经系统疾病与谷氨酸过度兴奋NMDA受体有关。广谱的NMDA受体拮抗剂能影响所有NMDA受体而产生不良反应，限制了其临床运用。NMDA受体NR2B亚单位在神经系统疾病中起着重要的作用，艾芬地尔等化合物能够选择性地作用于NMDA受体NR2B亚单位，将有可能发展成为临床上安全、有效的神经元保护剂。     

NMDA受体及其拮抗剂的研究进展

N-甲基-D-天冬氨酸(NMDA)受体是一种离子型谷氨酸受体,在中枢神经系统兴奋性的突触传递、可塑性和兴奋毒性中起着关键作用,与机体的记忆、学习和情绪密切相关.本文从结构分布和生理活性这两方面详细总结了N-甲基-D-天冬氨酸受体各亚型的特点,介绍并汇总了目前研究较多的N-甲基-D-天冬氨酸受体拮抗剂,为N-甲基-D-天...     

Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.     

Enhancement of NMDA-induced functional responses without concomitant NMDA receptor changes following chronic ethanol exposure in cerebellar granule cells

Primary cultures of rat cerebellar granule cells were used to investigate the effects of chronic ethanol exposure (50-100 mM for 3 days) on NMDA receptor functions (Ca2+ fluxes and neurotoxicity), binding parameters of the non-competitive NMDA receptor antagonist [3H]MK-801, relative abundance of mRNAs coding for NMDA receptor subunits, and expression of NMDA receptor subunit proteins. Ethanol exposure caused a marked increase in NMDA-produced neurotoxicity but produced a differential pattern of effects on NMDA-induced Ca2+ fluxes with a marked enhancement of NMDA-stimulated free cytoplasmic Ca2+ concentrations ([Ca2+]i), but no changes in NMDA-induced 45Ca2+ uptake. As shown by [3H]MK-801 binding experiments, chronic ethanol had no effect on affinity or number of the NMDA receptors. Furthermore, ethanol exposure had no effect on the relative abundance of the mRNAs for any of the NMDA receptor subunits (four splice variants of NR1, or NR2A-C), or on the expression of NMDA receptor subunit proteins. Our data confirm previous observations that chronic ethanol exposure enhances NMDA receptor-mediated neurotoxicity and elevation of [Ca2+]i, but also suggest that the increased responsiveness of NMDA receptors is not necessarily associated with alterations in the subunit composition or the ligand binding properties of NMDA receptors.     

Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes

The N-methyl-D-aspartate receptor-gated ion channel (NMDA channel) is regulated by glycine. To examine the interaction of glycine and NMDA receptor ligands on NMDA channel function, we used a biochemical marker of channel opening, [3H]N-(1-[thienyl]cyclohexyl)piperidine (TCP). We quantified [3H]glycine,L-[3H]glutamate, and TCP binding in an identical membrane preparation. This allowed direct comparison of NMDA and glycine receptor occupancy and channel activation. Glycine increased the association and dissociation rates of NMDA-dependent TCP binding to hippocampal membranes, without altering the Kd or Bmax for TCP binding. Structurally similar amino acids mimicked the action of glycine, with D-isomers being more potent than L-isomers. The potency of glycine in regulating TCP binding matched that for displacing [3H]glycine. Glycine stimulation of TCP binding required the presence of NMDA agonists and was inhibited by the NMDA antagonist D-2-amino-5-phosphonovaleric acid. Glycine stimulation of NMDA-dependent TCP binding was not associated with an increase in agonist binding to the NMDA receptor. Likewise, NMDA stimulation of glycine-dependent TCP binding was not associated with an increase in the binding of glycine to the glycine receptor. These findings permit the following conclusions: 1) glycine stimulates TCP binding solely by increasing the access of TCP to its site in the NMDA channel; 2) TCP binding can be used to quantify glycine regulation of the NMDA channel; 3) a stereospecific glycine receptor, as part of the NMDA receptor-channel complex, regulates NMDA-evoked channel opening by a mechanism not involving increased agonist binding to the NMDA receptor. Thus, it appears that the mechanism of glycine and NMDA receptor regulation of the NMDA channel is analogous to that of a two-key lock; both receptors, by independent and mutually required mechanisms, alter channel conformation to allow ion passage.