腺苷A2A受体的药理学

由不同类哺乳动物克隆获得的腺苷Ａ２Ａ受体被生理浓度的腺苷激活，进而刺激ｃＡＭＰ一其它介质的形成，嗜中性白细胞、血小板和务砭中均发现这类受体，中枢神经系统中某些细胞内含量尤其丰富。尾状它们与多巴胺Ｄ２受体共存，Ａ２Ａ受体的兴奋造成Ｄ２受体介导的神经传递的减低，作用于Ａ２Ａ受体的药物，可用于修饰对神经和精神疾病有重要关系的多巴胺能神经传递。本文论述了近期开发的Ａ２Ａ受体拮抗剂怎样用来阐明被Ａ２Ａ受体     

腺苷受体在纤维化疾病发病中的作用研究进展

纤维化可发生于多种器官,持续进展可致器官结构破坏和功能衰退,乃至器官衰竭,严重威胁人类健康和生命。腺苷是一种内源性嘌呤核苷,在人体各组织中均能生成,主要通过与4种不同的G-蛋白偶联受体结合,在体内发挥不同的作用。近来研究发现,腺苷受体(adenosine receptors,ARs)在组织再生和纤维化过程中发挥重要作用,了解这些过程可能在纤维化疾病的治疗上能发挥重要作用。该文就近年来对ARs在纤维化疾病中的研究进展进行讨论。     

腺苷及其受体在神经系统中的生物学作用

腺苷是一种在体内广泛存在的神经调质,特别在中枢神经系统中发挥着重要的作用。腺苷通过其不同类型的受体对睡眠、学习记忆、抑郁和焦虑等多种生理和病理过程产生影响。转基因技术的研究,使腺苷受体有可能成为治疗神经精神疾病的新靶点。     

哮喘患者外周血单个核细胞腺苷受体

目的通过检测哮喘患者外周血单个核细胞（PBMCs）腺苷受体mRNA表达,探讨腺苷受体在哮喘发病中的作用。方法用Ficoll液分离PBMCs,采用逆转录-多聚酶联反应法和图象分析半定量法检测PBMCs腺苷受体mRNA。结果正常人及哮喘患者PBMCs均表达A     

腺苷A3受体的研究进展

腺苷受体（ＡＲｓ）是Ｇ 白偶联受体的家族成员，它们能介导腺苷的多重生理作用。至今已经克隆出四种ＡＲ亚型：Ａ１，Ａ２Ａ，Ａ２Ｂ，Ａ３。本文重点介绍Ａ３亚型的生理、药理作用及其激动剂、拮抗剂的临床上的应用，如Ａ３的拮抗剂可治疗过敏、炎症，而激动剂可用于小脑的局部缺血及心肌预适应。     

靶向腺苷A2A受体的肿瘤免疫治疗研究进展

虽然免疫治疗现已成为对抗恶性肿瘤的革命性策略,但应答率不高,易产生耐受仍是制约肿瘤免疫治疗临床深入应用的瓶颈。不少研究表明,免疫抑制型肿瘤微环境和复杂的免疫逃逸机制是影响免疫检查点治疗效果和应答率的重要因素。因此,逆转肿瘤微环境障碍是提高免疫治疗应答率的关键。在肿瘤微环境中,胞外腺苷高水平的积累对免疫应答的抑制作用受到人们越来越多的关注。靶向腺苷受体,尤其是A_2AR亚型,可能是激活免疫应答、提高免疫治疗效果的有效策略。靶向腺苷-A_2AR通路可以增加免疫浸润,增强免疫细胞功能,将对免疫治疗不敏感的“冷肿瘤”部分逆转为“热肿瘤”,以增强治疗应答率并提高当前免疫治疗的疗效。目前,有不少的腺苷受体抑制剂已经在临床试验中显示出良好的效果,特别是与免疫检查点抑制剂、化疗和获得性细胞疗法的药物联用,有望为肿瘤免疫治疗带来新的突破。本文综述了肿瘤微环境中腺苷积累的方式、腺苷A_2A受体的作用和调控机制、腺苷A_2A受体抑制剂的临床试验进展和用药策略、靶向腺苷A_2A受体的潜在风险及其应用前景。     

半乳糖受体介导的肝靶向性研究进展

肝脏是人体内功能很多的腺体器官 ,参与体内消化、排泄、解毒和免疫调节等过程。肝脏疾病是临床上常见的疾病 ,有些肝脏疾病如病毒性肝炎、肝硬化和原发性肝癌等 ,极大地危害人民的健康。近年来 ,随着免疫学、微生物学、生物化学、药物学等学科及实验检测技术的发展 ,国内外对肝脏疾病的研究进展很快[1] 。而早在本世纪初 ,Ｅｈｒｉｃｈ就提出了导向药物的设想 ,即用某种具有特殊亲和力的载体把药物定向输送到靶器官发挥作用。治疗药物对靶细胞的特异性定位分布是药学领域的一个极富科技意义的挑战 ,大大改进了传统的给药方式[2 ] 。利用载…     

Adenosine,Adenosine Receptors and the Actions of Caffeine *

Abstract: Of the known biochemical actions of caffeine, only inhibition of adenosine receptors occurs at concentrations achieved during normal human consumption of the drug. Under normal physiological conditions, adenosine is present in sufficient concentrations to activate A₁ and A_2a receptors. Via actions on A, receptors, adenosine decreases neuronal firing and the release of neurotransmitters. The exact mechanisms are not known, but several possibilities are discussed. Via actions on A_2a receptors, adenosine - and hence caffeine - can influence dopaminergic neurotransmission. Caffeine can induce rapid changes in gene expression and, somewhat later, marked adaptive changes. These include antiepileptic and neuroprotective changes. Thus, caffeine has a number of central effects directly or indirectly related to adenosine receptors. Some of these are potentially useful, and drug development based on the actions of caffeine should be interesting.     

Hypertension Due to Blockade of Adenosine Receptors*

Abstract: Chronic treatment of rats with 90 μg/kg/day DPSPX (1,3‐dipropyl‐8‐sulphophenylxanthine) during seven days leads to a hypertensive state which is characterized by marked morphological changes of the blood vessel walls as well as by important functional alterations. While the angiotensin‐converting enzyme (ACE) inhibitor captopril and the antagonist of angiotensin II AT ₁ receptors losartan prevent the development of both hypertension and morphological changes, the selective β₁‐adrenoceptor antagonist atenolol could prevent only the increase in blood pressure. It is concluded that at least two factors are involved in the development of the hypertensive state.     

Advances in Antiviral Therapies Targeting Toll-like Receptors

Introduction: Organisms have evolved a rapid and non-specific way to defend themselves via Toll-like receptors (TLRs), which recognize specific signatures present on invading microbes and viruses. Once detected, these receptors flood the cell with cytokines and IFNs that not only help to eradicate the invading viruses but also activate the adaptive immune response. Owing to difficulties in viral detection, a whole class of TLRs is dedicated to sensing viral nucleic acids, while other TLRs detect viral coat proteins and aid in establishing antiviral immunity. To protect humans better, TLRs and their downstream mediators can be used as potential drug targets, which can be either activated or inhibited, to counter viral infections.

Areas covered: The current review focuses on TLR-targeting investigational drugs developed to treat viral diseases and virus-induced complications.

Expert opinion: TLRs are a good choice for eradicating viral infections because they can fine-tune the immune response. However, TLRs should be exploited carefully, as there have been instances where their activation has led to unwanted responses in terms of both immune and viral activation. Therefore, more focus should be placed on novel drugs that can induce significant and long-term immunity, while concomitantly alleviating side effects.     

Adenosine Stimulates Human Sperm Motility via A2 Receptors

Abstract— The effects of adenosine and its analogues on human sperm motility were studied using a transmembrane migration method. Specific binding sites for adenosine in human sperm were also investigated. Adenosine and 5′-N-ethylcarboxamidoadenosine (NECA) stimulated human sperm motility with similar efficacies and the maximal amplitudes of motility increases were both about 70%. 3,7-Dimethyl-1-propargylxanthine (DMPX), a potent A₂ antagonist, competitively antagonized NECA-induced motility stimulation. Successively higher concentrations of DMPX shifted the dose-response curve of NECA to the right in a nearly parallel fashion. Dipyridamole, an inhibitor of adenosine uptake, does not reduce the ability of adenosine to stimulate human sperm motility. In radioligand-binding studies, adenosine A₁ selective analogues, cyclopentyl-1,3-dipropylxanthine and 1-methyl-2-phenylethyl adenosine, have little competitive effect on [³H]NECA binding in human sperm membrane. These results provide evidence that adenosine enhances human sperm motility via adenosine A₂ receptors on the surface of sperm membranes.     

腺苷受体参与痛信息传递和调控的机制

腺苷受体是一类G蛋白耦联受体家族，有4个亚型，分别是A1、A2A、A2B、A3受体。腺苷受体广泛分布于神经系统，激活后在体内发挥不同的作用，如调节神经递质的释放、神经元的兴奋性、运动控制、情绪反应等。其中A1和A2A受体与痛信息的传递和调控密切相关，他们的选择性激动药和拮抗药具有良好的临床应用前景。因此，腺苷受体参与痛信息的传递和调控的机制成为人们关注和研究的焦点。     

Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy

BackgroundA dysfunction in glutamate neurotransmission is critical for seizure. Glutamate is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate acts via (i) ionotropic (iGlu) receptors, which are ligand-gated ion channels mediating fast excitatory synaptic transmission; and (ii) G proteins coupled metabotropic (mGlu) receptors.ObjectiveTo overview the evidence on the role of iGlu receptors in the onset, duration, and severity of convulsive and non-convulsive seizures to lay the groundwork for novel strategies for drug-resistant epilepsy.MethodsWe used PubMed crossed-search for “glutamate receptor and epilepsy” (sorting 3,170 reports), searched for “ionotropic glutamate receptors”, “AMPA receptors”, “NMDA receptors”, “kainate receptors”, “convulsive seizures”, “absence epilepsy”, and selected those papers focusing this Review’s scope.ResultsiGlu receptor antagonists inhibit, whereas agonists worsen experimental seizures in various animal species. Clinical development of iGlu receptor antagonists has been limited by the occurrence of adverse effects caused by inhibition of fast excitatory synaptic transmission. To date, only one drug (perampanel) selectively targeting iGlu receptors is marketed for the treatment of focal epilepsy. However, other drugs, such as topiramate and felbamate, inhibit iGlu receptors in addition to other mechanisms.ConclusionThis review is expected to help dissect those steps induced by iGlu receptors activation, which may be altered to provide antiepileptic efficacy without altering key physiological brain functions, thus improving the safety and tolerability of iGlu-receptor directed antiepileptic agents. This effort mostly applies to drug resistant seizures, which impact the quality of life and often lead to status epilepticus, which is a medical urgency.     

Interaction of Dihydropyridine Calcium Channel Agonists and Antagonists with Adenosine Receptors

Abstract: We have confirmed our previous ( Fredholm et al. 1986a ) finding that the dihydropyridine calcium channel agonist Bay K 8644 can displace [³H]-R-PIA from its binding site, the adenosine A₁-receptor. Bay K 8644 had an apparent K_i of 5.2 × 10^-6 M. The effect was shared by the two dihydropyridine calcium channel antagonists nifedipine and felodipine (K_i 4.2 and 8.7 × 10^-6 M, respectively). By contrast, two non-dihydropyridine calcium channel antagonists, verapamil and diltiazem, did not affect binding. Bay K 8644 displaced [³H]-R-PIA from its binding sites in a solubilized preparation. [³H]-XAC, a novel, potent A₁-receptor antagonist ligand, was also displaced by the dihydropyridine compounds with a similar or slightly higher potency as the displacement of R-PIA. This suggests a direct interaction with the adenosine receptor rather than an effect on regulatory GTP-binding proteins. However, at 1 μmol/l neither Bay K 8644 nor nifedipine significantly attenuated cyclic AMP accumulation in rat hippocampi or the R-PIA-mediated adenylate cyclase inhibition. The results show that dihydropyridine compounds that act as agonists or antagonists on L-type calcium channels can also affect adenosine receptors. The potency of the compounds for this effect is much lower than their potency as calcium channel agonists or antagonists. The results may therefore be of more experimental than clinical significance.     

Characterization of the Prejunctional Adenosine Receptors in the Rat Anococcygeus Muscle

Abstract— Adenosine receptor agonists inhibited electrically-evoked contractions of the rat isolated anococcygeus muscle. The compounds tested were: N⁶-cyclopentyladenosine (CPA), N((S, trans)-2-hydroxycyclopentyl)adenosine (GR79236), the R- and S-isomers of phenylisopropyladenosine (PIA), 5′-N-ethylcarboxamidoadenosine (NECA), ((2-(4-(2-carboxyethyl)phenyl)ethyl)amino)-N-ethylcarbox-amidoadenosine (CGS 21680) and N-((2-methylphenyl)methyl)adenosine (metrifudil). The rank order of agonist potency was: CPA = R-PIA = GR79236 = NECA » S-PIA > metrifudil > CGS 21680, which is consistent with an effect mediated by adenosine A₁ receptors. A similar rank order of potency was obtained for inhibition of electrically-evoked contractions of the guinea-pig ileum. However, there may be a lower receptor reserve in rat anococcygeus compared with the guinea-pig ileum, since higher concentrations of agonists were necessary to produce effects in the anococcygeus than in the guinea-pig ileum and S-PIA behaved as a partial agonist. The effect of NECA was antagonized in rat anococcygeus and guinea-pig ileum by the mixed A₁/A₂ receptor antagonist, 8-phenyltheophylline (pA₂ values of 6·8 and 6·9, respectively). The selective A₁-receptor antagonist, 8-cyclopentyl-l,3-dipropylxanthine (DPCPX), also blocked the inhibitory response to NECA in both tissues. Here, however, the pA₂ values (9·6 and 8·6, respectively) were slightly but significantly different. These values confirm that the prejunctional adenosine receptors of the rat anococcygeus are of the A₁ type, and suggest that they are similar but not necessarily identical to those of the guinea-pig ileum. The differing potencies of DPCPX as an antagonist of NECA between the preparations may reflect a tissue-dependent variation in sensitivity to this antagonist.     

Targeting the Dimerization of Epidermal Growth Factor Receptors with Small-Molecule Inhibitors

The epidermal growth factor (EGF) receptor is a receptor tyrosine kinase involved in the control of cell proliferation, and its overexpression is strongly associated with a variety of aggressive cancers. For example, 70–80% of metaplastic (cancer cells of mixed type) breast carcinomas overexpress EGF receptors. In addition, the EGF receptor is a highly significant contributor to common brain tumors (glioblastoma multiforme), both in initiation and progression (Huang P.H., Xu A.M., White F.M. (2009) Oncogenic EGFR signaling networks in glioma. Sci Signal;2:re6.). Brain metastases, an unmet medical need, are also common in metastatic cancer associated with overexpression of EGF receptors. Formation of EGF receptor homodimers is essential for kinase activation and was the basis for exploring direct inhibition of EGF receptor activation by blocking dimerization with small molecules. While inhibitors of protein/protein interactions are often considered difficult therapeutic targets, NSC56452, initially identified by virtual screening, was shown experimentally to inhibit EGF receptor kinase activation in a dose-dependent manner. This compound blocked EGF-stimulated dimer formation as measured by chemical cross-linking and luciferase fragment complementation. The compound was further shown to inhibit the growth of HeLa cells. This first-generation lead compound represents the first drug-like, small-molecule inhibitor of EGF receptor activation that is not directed against the intracellular kinase domain.