Structure-affinity relationships of adenosine A2B receptor ligands

Many selective and high affinity agonists and antagonists have been developed for the adenosine A(1), A(2A), and A(3) receptors. Very recently such compounds have been identified for the adenosine A(2B) receptors. This review presents an overview of the structure-affinity relationships of antagonists and agonists for this receptor subtype as published in the scientific and patent literature. To date the most selective >370-fold, high affinity adenosine A(2B) receptor antagonist is the xanthine analog, compound 16 (8-(1-(3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione). The pyrrolopyrimidine analog OSIP339391 (73) is slightly less selective, 70-fold, but has a higher affinity 0.41 nM compared to 1 nM for compound 16. Other promising classes of compounds with selectivities ranging from 10- to 160-fold and affinities ranging from 3 to 112 nM include triazolo, aminothiazole, quinazoline, and pyrimidin-2-amine analogs. Progress has also been achieved concerning the development of selective high affinity agonists for the adenosine A(2B) receptor. For years the most potent, albeit non-selective adenosine A(2B) receptor agonist was (S)PHPNECA (88). Last year, a new class of non-ribose ligands was reported. Several compounds displayed selectivity with respect to adenosine A(2A) and A(3) receptors. In addition, full and partial agonists for the adenosine A(2B) receptor were identified with EC(50) values of 10 nM (LUF5835, 103) and 9 nM (LUF5845, 105), respectively.     

Competitive AMPA receptor antagonists

Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature.     

Comparison of angiotensin II receptor antagonists

Nonpeptide orally active angiotensin II type 1 (AT1) receptor antagonists are the most specific means presently available to block the renin-angiotensin enzymatic cascade. Six of these drugs have already been licensed in Europe and in the United States for the treatment of high blood pressure, and additional candidates are in the pipeline. The World Health Organisation has also recently endorsed their use for this condition. Inasmuch as AT1 receptor antagonists have proven themselves the equals of angiotensin converting enzyme inhibitors with respect to antihypertensive efficacy, but demonstrated better safety profiles, this class of drugs may be considered to be a qualitative improvement in the treatment of essential hypertension. Interestingly, the six agents now on the market diverge considerably with respect to their pharmacokinetic and pharmacodynamic properties, although it is not certain whether such differences are clinically relevant. A considerable number of large, multicentre trials are in progress to ascertain the possible longer-term organoprotective effects of these substances on cardiovascular morbidity and mortality. Because of their noteworthy safety record to date, and simple once-a-day dosage regimen, AT1 receptor antagonists have the potential to improve compliance in patients with chronic hypertension.     

A 2A adenosine receptor regulates glia proliferation and pain after peripheral nerve injury

Peripheral nerve injury produces a persistent neuropathic pain state characterized by spontaneous pain, allodynia and hyperalgesia. In this study, we evaluated the possible involvement of A 2ARs in the development of neuropathic pain and the expression of microglia and astrocytes in the spinal cord after sciatic nerve injury. For this purpose, partial ligation of the sciatic nerve was performed in A 2A knockout mice and wild-type littermates. The development of mechanical and thermal allodynia, as well as thermal hyperalgesia was evaluated by using the von Frey filament model, the cold-plate test and the plantar test, respectively. In wild-type animals, sciatic nerve injury led to a neuropathic pain syndrome that was revealed in these three nociceptive behavioural tests. However, a significant decrease of the mechanical allodynia and a suppression of thermal hyperalgesia and allodynia were observed in A 2AR deficient mice. The expression of microglia and astrocytes was enhanced in wild-type mice exposed to sciatic nerve injury and this response was attenuated in knockout animals. Taken together, our results demonstrate the involvement of A 2ARs in the control of neuropathic pain and propose this receptor as an interesting target for the development of new drugs for the management of this clinical syndrome.     

白三烯受体拮抗剂在慢性咳嗽治疗中的临床价值

目的 探讨白三烯受体拮抗剂在慢性咳嗽临床治疗中的意义.方法 选择81例慢性咳嗽患者(根据慢性咳嗽诊断流程诊断),所有患者均符合咳嗽时间≥8周,不吸烟或戒烟4周以上,无服用血管紧张素转换酶抑制剂类药物史,服用者停药观察4周,X线胸片检查未见异常,并除外胃食管反流性咳嗽、除变应性鼻炎的其他上气道咳嗽综合征、支气管内膜结核等其他慢性咳嗽病因.对诊断为咳嗽变异性哮喘、变应性鼻炎、嗜酸粒细胞性支气管炎及感染后咳嗽的患者给予孟鲁司特钠10 mg,每晚1次进行治疗4周并观察疗效.结果 81例入选患者中咳嗽变异性哮喘36例,变应性鼻炎30例,嗜酸粒细胞性支气管炎5例,感染后咳嗽10例.经孟鲁司特钠治疗后,67例患者咳嗽症状临床控制,12例患者显效,2例无效,有效率97.5%(79/81).结论 气道炎症是慢性咳嗽患者常见的病理特征,白三烯受体拮抗剂孟鲁司特钠有显著的抗炎作用,能明显改善咳嗽变异性哮喘、嗜酸粒细胞性支气管炎、感染后咳嗽、变应性鼻炎等慢性咳嗽患者的气道炎症,减轻咳嗽症状,是治疗慢性咳嗽的重要药物.     

Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice.

Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.     

LGR4基因调控小鼠肺组织糖皮质激素受体表达及肺发育

目的：探讨LGR4基因缺失引起新生小鼠纯亡的原因及其可能的机制。方法：观察LGR4基因敲除（KO）小鼠出生后48h内的表现，记录其死亡时间，并对不同基因型小鼠进行生存分析。取LGR4 KO纯合的新生小鼠及不同胚胎期小鼠的肺脏进行病理切片和HE染色，观察其组织形态学改变，诈耳簪结果与基因型为野生型（WT）、杂合型的小鼠比较。采用ELISA法检测LGR4 KO纯合小鼠、WT小鼠血清中皮质酮水平，并用蛋白印迹（Western blot）半定量检测小鼠胎肺中糖皮质激素受体（GR）的蛋白水平。结果：LGR4 KO纯合小鼠出生后出现不同程度的呼吸困难、紫绀等表现，52．2％的LGR4 KO纯合小鼠在出生后28h内死亡：组织学检查发现，LGR4 KO纯合小鼠的肺脏在胚胎晚期和新生期存在明显的结构异常，包括肺泡减少、肺间隔增厚、细胞密度增加。此外，LGR4缺失还引起小鼠胚胎晚期肺中GR水平明显下调，但其对小鼠肾上腺的皮质酮分泌功能并无显著影响。结论：LGR4缺失可引起小鼠肺胚胎晚期发育障碍和新生小鼠肺结构异常，导致小鼠出生后早期死亡，而GR水平的下调可能是其重要机制。     

血小板P2Y_(12)受体拮抗剂的研究进展

血小板聚集在血栓形成过程中发挥关键作用,抗血小板药物是预防和治疗动脉粥样硬化疾病患者发生严重心血管事件的重要基石。P2Y12受体拮抗剂是一类重要的抗血小板药物,近年来成为研究的热点并在临床上广泛应用。本文结合最新研究进展,对P2Y12受体拮抗剂作用机制、药理学特征、临床疗效及安全性进行综述,以期为临床合理用药提供参考。     

Adipokinetic hormone signalling system in the Chagas disease vector,Rhodnius prolixus

Neuropeptides and their G protein‐coupled receptors are widespread throughout Metazoa and in several cases, clear orthologues can be identified in both protostomes and deuterostomes. One such neuropeptide is the insect adipokinetic hormone (AKH), which is related to the mammalian gonadotropin‐releasing hormone. AKH has been studied extensively and is known to mobilize lipid, carbohydrates and proline for energy‐consuming activities such as flight. In order to determine the possible roles for this signalling system in Rhodnius prolixus, we isolated the cDNA sequences encoding R. prolixus AKH (Rhopr‐AKH) and its receptor (Rhopr‐AKHR). We also examined their spatial expression pattern using quantitative PCR. Our expression analysis indicates that Rhopr‐AKH is only expressed in the corpus cardiacum of fifth‐instars and adults. Rhopr‐AKHR, by contrast, is expressed in several peripheral tissues including the fat body. The expression of the receptor in the fat body suggests that AKH is involved in lipid mobilization, which was confirmed by knockdown of Rhopr‐AKHR via RNA interference. Adult males that had been injected with double‐stranded RNA (dsRNA) for Rhopr‐AKHR exhibited increased lipid content in the fat body and decreased lipid levels in the haemolymph. Moreover, injection of Rhopr‐AKH in Rhopr‐AKHR dsRNA‐treated males failed to elevate haemolymph lipid levels, confirming that this is indeed the receptor for Rhopr‐AKH.     

C-peptide: new findings and therapeutic implications in diabetes

In contrast to earlier views, new data indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. C-peptide in nanomolar concentrations binds specifically to cell membranes, probably to a G-protein coupled receptor. Ca(2+)- and MAP-kinase dependent signalling pathways are activated, resulting in stimulation of Na(+), K(+)-ATPase and endothelial nitric oxide (NO) synthase, two enzyme systems known to be deficient in diabetes. C-peptide may also interact synergistically with insulin signal transduction. Studies in intact animals and in patients with type 1 diabetes have demonstrated multifaceted effects. Thus, C-peptide administration in streptozotocin-diabetic animals results in normalization of diabetes-induced glomerular hyperfiltration, reduction of urinary albumin excretion and diminished glomerular expansion. The former two effects have also been observed in type 1 diabetes patients given C-peptide in replacement dose for up to 3 months. Peripheral nerve function and structure are likewise influenced by C-peptide administration; sensory and motor nerve conduction velocities increase and nerve structural changes are diminished or reversed in diabetic rats. In patients with type 1 diabetes, beneficial effects have been demonstrated on sensory nerve conduction velocity, vibration perception and autonomic nerve function. C-peptide also augments blood flow in several tissues in type 1 diabetes via its stimulation of endothelial NO release, emphasizing a role for C-peptide in maintaining vascular homeostasis. Continued research is needed to establish whether, among the hormones from the islets of Langerhans, C-peptide is the ugly duckling that--nearly 40 years after its discovery--may prove to be an endogenous peptide hormone of importance in the treatment of diabetic long-term complications.     

Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists

Antiplatelet agents like aspirin and adenosine diphosphate receptor antagonists are effective in reducing recurrent ischemic events. Considerable inter‐individual variability in the platelet inhibition obtained with these drugs has initiated a search for explanatory mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms have been linked with reduced platelet inhibition and lack of clinical efficacy of antiplatelet drugs, particularly clopidogrel and aspirin. Consequently, attempts to adjust antiplatelet treatment according to genotype have been made, but the clinical benefit has been modest in studies performed so far. The progress in genome science over the last decade and the declining cost of sequencing technologies hold the promise of enabling genetically tailored antiplatelet therapy. However, more evidence is needed to clarify which polymorphisms may serve as targets to improve treatment. The present review outlines the panel of polymorphisms affecting the benefit of aspirin and adenosine diphosphate receptor antagonists, including novel and ongoing studies evaluating whether genotyping may be beneficial in tailoring antiplatelet therapy.     

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology,medicinal chemistry,and in silico approaches

Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A₁, A_2A, A_2B, and A₃. Among these G protein‐coupled receptors, the A₃ subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A₃ adenosine receptor (AR), together with an overview on the progress of hA₃AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure–activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA₃AR and drug design. © 2011 Wiley Periodicals, Inc. Med Res Rev     

腺苷A1受体参与单次电针预处理诱导的脑急性缺血耐受

目的:探讨腺苷A1受体是否参与单次电针预处理诱导的脑急性缺血耐受.方法:40只健康雄性SD大鼠(280～320 g)随机分为对照组(C)、8-环戊基-1,3-二丙基黄嘌呤(DPCPX)-缺血组(DI)、电针组(EA)、二甲基亚砜(DMSO)-电针组(DME)和DPCPX-电针组(DPE)5组(n=8):C组给予大脑中动脉栓塞(MCAO)前3 h腹腔注射质量分数为1%的戊巴比妥钠40 mg/kg和生理盐水1 ml/kg,DI组给予1%戊巴比妥钠40 mg/kg和质量分数为0.1%的DPCPX 1 mg/kg;EA组、DME组和DPE组分别于电针刺激百会穴前30 min腹腔注射生理盐水1 ml/kg、DMSO 1 ml/kg和0.1%的DPCPX 1 mg/kg,3组均在腹腔注射1%戊巴比妥钠40 mg/kg麻醉下电针刺激百会穴30 min后2 h给予局灶性脑缺血.采用颈内动脉尼龙线线栓法致大脑中动脉栓塞(120 min)模型,观察再灌注后24 h时神经功能缺损评分,并取大脑行2,3,5-氯化三苯四唑(TTC)染色以测量脑梗死容积.结果:术后动物均存活.EA组和DME组再灌注24 h时神经功能缺损评分明显低于对照组(P<0.01和P<0.05),脑梗死容积也都明显小于对照组(P均<0.05);而DI组和DPE组与对照组比较神经功能缺损评分和脑梗死容积均无显著性差异.结论:单次电针刺激百会穴诱导大脑急性缺血耐受可能通过腺苷A1受体相关机制介导.     

Src family kinases are essential for primary aggregation by Gi‐coupled receptors

Summary. Introduction and Background: Adrenaline stimulates biphasic aggregation in plasma through the G_i‐coupled α_2A‐adrenoreceptor. In the present study, we demonstrate that both primary and secondary wave aggregation induced by adrenaline in plasma is blocked by two structurally distinct inhibitors of Src family kinases, dasatinib and PD0173952. Methods and Results: In contrast, primary aggregation is partially inhibited or unaffected in the presence of inhibitors of cyclo‐oxygenase, phosphoinositide (PI) 3‐kinases, and P2Y₁ and P2Y₁₂ ADP receptors, although secondary aggregation is abolished. The ability of adrenaline to inhibit adenylyl cyclase and to synergize with platelet agonists in mediating platelet activation in plasma is retained in the presence of Src family kinase inhibition. Moreover, adrenaline does not activate Src family kinases, as determined by western blotting of their regulatory tyrosines, suggesting that constitutive signaling from Src family kinases may underlie their role in activation. Adrenaline is widely used in clinical laboratories for investigation of patients with suspected bleeding disorders. In a group of 90 unrelated patients with a clinically diagnosed platelet bleeding disorder, we identified four who did not exhibit primary wave aggregation in response to adrenaline, although the catecholamine potentiated the response to other agonists, and five who failed to undergo secondary wave aggregation. In contrast, adrenaline stimulated biphasic aggregation in 60 controls. All of the patients with a defective response to adrenaline had impaired ADP‐induced platelet activation. Conclusions: The present results indicate a previously unappreciated role for Src family kinases in mediating G_i signaling in plasma, and demonstrate heterogeneity in response to adrenaline in patients with a clinically diagnosed platelet disorder.     

Small molecule antagonists for chemokine CCR3 receptors

The chemokine receptor CCR3 is believed to play a role in the development of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis. Despite the conflicting results that have been reported regarding the importance of eosinophils and CCR3 in allergic inflammation, inhibition of this receptor with small molecule antagonists is thought to provide a valuable approach for the treatment of these diseases. This review describes the structure–activity relationships (SAR) of small molecule CCR3 antagonists as reported in the scientific and patent literature. Various chemical classes of small molecule CCR3 antagonists have been described so far, including (bi)piperidine and piperazine derivatives, N‐arylalkylpiperidine urea derivatives and (N‐ureidoalkyl)benzylpiperidines, phenylalanine derivatives, morpholinyl derivatives, pyrrolidinohydroquinazolines, arylsulfonamides, amino‐alkyl amides, imidazole‐ and pyrimidine‐based antagonists, and bicyclic diamines. The (N‐ureidoalkyl)benzylpiperidines are the best studied class in view of their generally high affinity and antagonizing potential. For many of these antagonists subnanomolar IC₅₀ values were reported for binding to CCR3 along with the ability to effectively inhibit intracellular calcium mobilization and eosinophil chemotaxis induced by CCR3 agonist ligands in vitro. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 5, 778–817, 2010     

Recent advances in selective opioid receptor agonists and antagonists

Opioid analgesics provide outstanding benefits for relief of severe pain. The mechanisms of the analgesia accompanied with some side effects have been investigated by many scientists to shed light on the complex biological processes at the molecular level. New opioid drugs and therapies with more desirable properties can be developed on the bases of accurate insight of the opioid ligand-receptor interaction and clear knowledge of the pharmacological behavior of opioid receptors and the associated proteins. Toward this goal, recent advances in selective opioid receptor agonists and antagonists including opioid ligand-receptor interactions are summarized in this review article.     

Mechanisms of pain modulation by sex hormones in migraine

A number of pain conditions, acute as well as chronic, are much more prevalent in women, such as temporomandibular disorder (TMD), irritable bowel syndrome, fibromyalgia, and migraine. The association of female sex steroids with these nociceptive conditions is well known, but the mechanisms of their effects on pain signaling are yet to be deciphered. We reviewed the mechanisms through which female sex steroids might influence the trigeminal nociceptive pathways with a focus on migraine. Sex steroid receptors are located in trigeminal circuits, providing the molecular substrate for direct effects. In addition to classical genomic effects, sex steroids exert rapid nongenomic actions to modulate nociceptive signaling. Although there are only a handful of studies that have directly addressed the effect of sex hormones in animal models of migraine, the putative mechanisms can be extrapolated from observations in animal models of other trigeminal pain disorders, like TMD. Sex hormones may regulate sensitization of trigeminal neurons by modulating expression of nociceptive mediator such as calcitonin gene-related peptide. Its expression is mostly positively regulated by estrogen, although a few studies also report an inverse relationship. Serotonin (5-Hydroxytryptamine [5-HT]) is a neurotransmitter implicated in migraine; its synthesis is enhanced in most parts of brain by estrogen, which increases expression of the rate-limiting enzyme tryptophan hydroxylase and decreases expression of the serotonin re-uptake transporter. Downstream signaling, including extracellular signal-regulated kinase activation, calcium-dependent mechanisms, and cAMP response element-binding activation, are thought to be the major signaling events affected by sex hormones. These findings need to be confirmed in migraine-specific animal models that may also provide clues to additional ion channels, neuropeptides, and intracellular signaling cascades that contribute to the increased prevalence of migraine in women.