磷酸二酯酶2对抑郁焦虑及认知障碍等中枢神经疾病的调节作用

磷酸二酯酶（Phosphodiesterase,PDE）水解细胞内第二信使-环磷酸腺苷和环磷酸鸟苷,降低细胞内第二信使的含量,进而影响下游信号转导,调节细胞内的生命活动。磷酸二酯酶2（PDE2）是磷酸二酯酶大家族的成员之一,在中枢神经系统中分布广泛,尤其在海马和杏仁核部分密集,近年来越来越多的研究表明PDE2可能参与中枢神经系统疾病的调节,而相应的PDE2抑制剂可能具有治疗抑郁、焦虑和学习记忆障碍等中枢神经系统疾病前景。本文综述了PDE2在中枢神经系统疾病调节中的作用及其抑制剂在治疗相关疾病的应用。     

磷酸二酯酶4及其抑制剂在学习记忆中的作用

环核苷酸磷酸二酯酶(phosphodiesterase,PDE)是环核苷酸的唯一细胞内水解酶,因而PDE抑制剂可以通过阻碍环核苷酸的分解,参与生物功能的调节。磷酸二酯酶4(PDE4)是PDE大家族的成员之一,PDE4抑制剂在临床上主要用于治疗慢性阻塞性肺病(COPD)、哮喘、自身免疫性疾病(如银屑病)、过敏性疾病及抑郁症。近年来,越来越多的研究表明PDE4可以通过多种途径影响学习记忆的过程,相应的抑制剂能够通过调控细胞内cAMP水平来改善中枢神经系统退行性疾病所致的学习记忆障碍。本文综述了PDE4在学习记忆调节中的作用及其抑制剂在治疗学习记忆障碍疾病中的应用。     

磷酸二酯酶4研究进展

环腺苷酸(cAMP)和环鸟苷酸(cGMP)对于细胞的许多功能有重要作用。磷酸二酯酶(PDEs)催化cAMP和cGMP水解开环分别生成AMP和GMP,这是细胞内降解cAMP和cGMP的唯一途径。PDEs可分为11个家族,其中有8个家族可以水解cAMP,包括能专一性地水解cAMP的PDE家族(如PDE4),和既可水解cAMP又可水解cGMP的PDE家族。PDE4同工酶主要存于在炎症细胞中。PDE4可分为A、B、C、D 4个亚家族,根据其N端的特殊结构,有长、短和超短三种形式。PDE4催化区三维结构的阐明有助于它们功能的研究和相关药物的设计。PDE4通过与其它蛋白如抑制蛋白、A激-酶锚定蛋白(AKAP)以及活化的C激酶1受体(RACK1)等相互作用使cAMP浓度区域化,选择性地调节各种细胞功能。PDE4作为一个治疗靶点,研究其选择性抑制剂具有重要的意义,可以用于治疗由炎症引起的疾病,如哮喘、慢性阻塞性肺疾病(COPD)、阿尔采末病(AD)、帕金森病(PD)和中风等由潜在的炎症引起神经元受损造成的中枢神经系统疾病。     

磷酸二酯酶4抑制剂对阿尔茨海默病、抑郁症及二者共病的潜在治疗作用及其机制研究进展

磷酸二酯酶4(PDE4)作为PDE家族中数量最多的一类成员,特异性水解细胞内第二信使环磷酸腺苷（cAMP）,并参与多种生理功能的调节,在中枢神经系统疾病的发生发展中发挥重要作用。近年研究表明,PDE4是治疗抑郁症及记忆和认知障碍等神经精神疾患的重要靶点。通过调控PDE4的活性和表达使脑内cAMP表达水平及cAMP介导的信号通路恢复正常,将为阿尔茨海默病、抑郁症及二者共病等神经精神疾病提供重要的治疗策略。本文对PDE4与这些疾病之间关系的最新研究进展进行综述和讨论,为阿尔茨海默病、抑郁症及二者共病的预防和治疗提供新的思路及对策。     

磷酸二酯酶7:一个新的抗炎免疫药物靶点研究进展

磷酸二酯酶(phosphod iesterases,PDEs)作为体内特异性水解第二信使cAMP和cGMP的唯一蛋白酶家族,参与多种生理病理过程。研究表明PDE7是cAMP特异性的,分为PDE7A、PDE7B两个亚型,主要分布在免疫和炎症细胞中。PDE7作为一个新的潜在抗炎免疫药物靶点,其选择性抑制剂有可能用于治疗慢性阻塞性肺疾病(COPD)、类风湿性关节炎、阿尔采末病(AD)等与免疫炎症密切相关的疾病。     

磷酸二酯酶:从伟哥到抗阿尔茨海默病药物

磷酸二酯酶(PDE)是一个催化第二信使c AMP和/或c GMP水解的超级酶家族。它包括11个家族(PDE1～PDE11),对调节细胞内cAMP和cGMP水平发挥关键作用。PDE研究半个世纪以来,其靶位功能越发明显并受到重视。尤其是靶位PDE5的伟哥(Viagra,sildenafil;PDE5抑制剂)研制成功,使PDE研究成为国际药物研发的一大热点。PDE4抑制剂罗氟司特(roflumilast,Daxas~?)和apremilast(Otezla~?)分别成功用于治疗慢性阻塞性肺疾患(COPD)和银屑病及银屑病性关节炎,再次证明PDE作为药物靶标的重要研究价值和临床应用前景。阿尔茨海默病(AD)是一种慢性进行性神经退行性疾病,以记忆和认知能力的进行性减退为主要临床特征。研究表明,PDE2,PDE4,PDE5,PDE7,PDE9和PDE11都不同程度地参与AD学习记忆和认知的调节,其中尤以PDE4作用明显而广泛。PDE4有4种亚型(PDE4A～D),由不同基因编码。PDE4D研究相对较多。基因敲除或敲减PDE4D可改善AD小鼠的学习记忆障碍及抑郁等行为;对PDE4D有选择性抑制作用的化合物也有类似作用,提示PDE4D可能是治疗AD的重要靶标。然而,PDE4D也参与中枢性呕吐作用的调节。最新研究表明,通过别构抑制PDE4D可以达到既对抗AD小鼠的记忆下降,又不至于产生呕吐等副反应。这可能是抗AD药物研究的一个重要方向。     

磷酸二酯酶在慢性疼痛与阿尔茨海默病共病中的作用研究进展

慢性疼痛与阿尔茨海默病（AD）是困扰人类的两大疾病。流行病学调查显示,慢性疼痛患者常伴有情感和认知功能异常,而AD患者也常伴有慢性疼痛,这提示慢性疼痛与AD可能存在相似或共同的病理生理机制,但其详细机制尚不明确。磷酸二酯酶（PDE）具有特异性水解细胞内第二信使环磷酸腺苷（cAMP）和（或）环磷酸鸟苷（cGMP）的功能。最新研究报道,PDE家族中PDE2,4,5或7亚型可通过激活cAMP/蛋白激酶A和（或）cGMP/蛋白激酶G,促进其下游信号通路磷酸腺苷反应元件结合蛋白的磷酸化和脑源性神经营养因子的表达,从而不同程度地改善AD小鼠的认知功能障碍,缓解慢性疼痛小鼠的痛觉异常。本文综述PDE在慢性疼痛和AD共病中的作用及相关机制。     

磷酸二酯酶抑制剂

环腺苷酸(cAMP)为中介细胞对各种激素和神经递质的效应的第二信使。它调节各种代谢过程,包括心肌和平滑肌的收缩、糖原分解、血小板聚集、分泌作用与脂肪分解作用。环鸟苷酸(cGMP)的效应与cAMP相对抗。磷酸二酯酶(PDE)抑制剂抑制PDE水解cAMP,再现cAMP的效应。近年来研究了细胞中三类不同分子形式的PDE,它们的底物特异性不同(cAMP或cGMP),在细胞中的定位(可溶性或与膜结合)不同,对调钙蛋白的反应也不同。不同分子形式的PDE     

磷酸二酯酶5抑制剂的研究进展

环腺苷酸（cAMP）和环鸟苷酸（cGMP）是重要的细胞内第二信使，其在细胞内水平的高低对调节细胞的各种功能具有重要意义。参与调节细胞内cAMP和cGMP水平的酶类包括腺苷酸环化酶（AC）、鸟苷酸环化酶（GC）和磷酸二酯酶（PDE）。这几种酶的平衡使细胞内的cAMP和cGMP水平维持在正常范围（图1）。在某些疾病状态下如高血压、心绞痛等可发现细胞内cAMP和cGMP水平下降。为提高细胞内cAMP和cGMP的水平，可通过激动AC、GC和抑制PDE两种途径来实现，且第二种途径效果更佳。近年来，人们对研究和开发PDE抑制剂表现出极大热情，并…     

新型磷酸二酯酶特异性抑制剂的发现及识别机制

磷酸二酯酶(PDE)通过催化水解细胞内第二信使(环磷酸腺苷cAMP,或环磷酸鸟苷cGMP),以降低细胞内cAMP或cGMP的浓度,从而中止这两个第二信使所传导的生理作用。PDEs作为新型的药物作用靶点,参与多种疾病的治疗,已成为新药研发的重要靶点。截至目前,已有多个PDE抑制剂药物上市(PDE5:5个,治疗性功能障碍和肺动脉高压;PDE4:3个,治疗慢性阻塞性肺病等),其中最出名的案例是用于治疗男性勃起功能障碍和肺动脉高压的PDE5抑制剂西地那非。然而,低选择性是这些PDE抑制剂的主要缺陷。近期我们针对PDE4,5,8,9和10等亚型,通过基于结构的药物分子设计,合成并发现多类高选择性的抑制剂。如,1)合成近150个PDE9抑制剂,从中发现抑制效应最强的高选择性先导结构3r。3r(IC_(50)=0.6 nmol·L~(-1),对PDE1选择性为788倍),活性和选择性均明显优于临床Ⅱ期的辉瑞抑制剂PF-04447943。通过晶体结构分析,发现3r与PDE9特有残基Y424形成氢键,是其具有高倍选择性的结构基础,这为PDE9高选择性抑制剂提供了新的设计策略。此外共晶结构还揭示3r和A452形成一个氢键,而PF-04447943未显示这种结合模式。通过设计与A452形成氢键,可提高化合物的抑制效应。2)合成近100个多个PDE5抑制剂,从中发现抑制剂从中发现抑制效应最强的高选择性先导结构1610。1610(IC_(50)=5.0 nmol·L~(-1),对PDE6选择性为100倍)的抑制活性与辉瑞药物西地那非相当,但选择性均明显优于西地那非(对PDE6选择性为2~3倍),动物实验也显示该类药物的抗动脉高压效果明显优于对照药物西地那非。通过分子模拟分析,发现1610进入靶标结构的Q2口袋,是1610具有100倍选择性的结构基础,这为PDE5高选择性抑制剂提供了新的设计策略。     

Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that are involved in the regulation of the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) by controlling their rates of hydrolysis. There are 11 different PDE families and each family typically has multiple isoforms and splice variants. The PDEs differ in their structures, distribution, modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown to play distinct roles in processes of emotion and related learning and memory processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or cGMP, modulate mood and related cognitive activity. This review discusses the current state and future development in the burgeoning field of PDEs in the central nervous system. It is becoming increasingly clear that PDE inhibitors have therapeutic potential for the treatment of neuropsychiatric disorders involving disturbances of mood, emotion, and cognition.     

Improving memory: a role for phosphodiesterases

During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.     

Section Review: Cardiovascular & Renal: Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases

Cyclic nucleotide phosphodiesterases (PDEs) comprise at least seven families of isozymes coded by related but distinct genes, grouped on the basis of their structural and enzymatic characteristics. Five of these families are known to be present in the cardiovascular system. A number of potent inhibitors have been synthesised with relative selectivity for some PDEs. However, there is no selective inhibitor of PDE1 (calmodulin-activated), and only one compound has been reported which selectively inhibits PDE2 (stimulated by cGMP). Available information is limited to pharmacological and therapeutic properties of drugs selectively inhibiting two PDEs specific for cAMP (PDE3, inhibited by milrinone-like cardiotonics, and PDE4, inhibited by rolipram) and a cGMP-PDE (PDE5, inhibited by zaprinast). Differential expression of PDEs and differential subcellular localisation provide the possibility of selectively targeting cardiovascular and platelet functions with selective PDE inhibitors. The resulting effects include short- and long-term modulation of cardiac and vascular inotropy, cardiac rhythm and exoitability, thrombosis, inflammatory responses to injury and, probably, proliferation of vascular smooth muscle cells. PDE3 inhibitors have been investigated in heart failure. Despite leading to marked haemodynamic improvement, chronic treatment with PDE3 inhibitors does not increase (and may even decrease) survival, due to arrhythmias (probably induced by excessive cAMP accumulation). PDE4 inhibitors are being actively investigated in inflammatory diseases. Their actions in endothelial cells may also lead to antithrombotic effects. PDE5 inhibitors might compensate the pathological impairment of nitric oxide-induced cGMP levels seen in atherosclerosis and after endothelial injury. Preclinical studies suggest that they may reduce myointimal proliferation after angioplasty. Identification of isozymes expressed in each tissue and determination of their possible pathological alterations will probably be possible in the near future. This will afford clarification of the role of PDEs in the cardiovascular system and the potential therapeutic uses of PDE inhibitors.     

Targeting Phosphodiesterases in Anti-platelet Therapy

There are two primary modes of platelet inhibition: blockade of membrane receptors or neutralization of intracellular pathways. Both means of inhibition have proven benefits in the prevention and resolution of atherothrombotic events. With regard to intracellular inhibition, phosphodiesterases (PDEs) are fundamental for platelet function. Platelets possess several PDEs (PDE2, PDE3 and PDE5) that catalyze the hydrolysis of cyclic adenosine 3'-5'-monophosphate (cAMP) and cyclic guanosine 3'-5'-monophosphate (cGMP), thereby limiting the levels of intracellular nucleotides. PDE inhibitors, such as cilostazol and dipyridamole, dampen platelet function by increasing cAMP and cGMP levels. This review focuses on the roles of PDE inhibitors in modulating platelet function, with particular attention paid to drugs that have anti-platelet clinical indications.     

Phosphodiesterase inhibitors in airways disease

Phosphodiesterases hydrolyse intracellular cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into inactive 5' monophosphates, and exist as 11 families. They are found in a variety of inflammatory and structural cells. Inhibitors of PDEs allow the elevation of cAMP and cGMP which lead to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation or of immune responses. PDE4 inhibitors specifically prevent the hydrolysis of cAMP, and PDE4 isozymes are present in inflammatory cells. Selective PDE4 inhibitors have broad spectrum anti-inflammatory effects such as inhibition of cell trafficking, cytokine and chemokine release from inflammatory cells, such as neutrophils, eosinophils, macrophages and T cells. The second generation PDE4 inhibitors, cilomilast and roflumilast, have reached clinical trial stage and have some demonstrable beneficial effects in asthma and chronic obstructive pulmonary disease (COPD). The effectiveness of these PDE4 inhibitors may be limited by their clinical potency using doses that have minimal effects on nausea and vomiting. Topical administration of PDE4 inhibitors may provide a wider effective to side-effect profile. Development of inhibitors of other PDE classes, combined with PDE4 inhibition, may be another way forward. PDE5 is an inactivator of cGMP and may have beneficial effects on hypoxic pulmonary hypertension and vascular remodelling. PDE3 and PDE7 are other cAMP specific inactivators of cAMP. PDE7 is involved in T cell activation and a dual PDE4-PDE7 inhibitor may be more effective in asthma and COPD. A dual PDE3-PDE4 compound may provide more bronchodilator and bronchoprotective effect in addition to the beneficial PDE4 effects.     

Anti-platelet therapy: phosphodiesterase inhibitors

Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme-selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol.     

Role of phosphodiesterase isoenzymes in the control of renin secretion: effects of selective enzyme inhibitors.

In most cells, the steady-state level of cAMP ultimately depends on the rate of cAMP synthesis by adenylyl cyclase and the rate of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). PDEs exist in multiple forms that have been grouped into seven families based on their substrate specificity, mode of regulation and kinetic properties. Selective inhibitors of many PDE families are now available. Examples are milrinone and trequinsin (PDE3); rolipram and Ro 20-1724 (PDE4); and zaprinast, sildenafil and didyridamole (PDE5). These inhibitors have proven to be valuable tools to investigate the role of PDEs in cell function. Representatives of most PDE families are present in the kidneys, and recent studies in this and other laboratories have provided evidence that some of them participate in the regulation of renin secretion. In particular, administration of selective PDE inhibitors has marked effects on renin secretion. For example, the PDE3 inhibitors milrinone and trequinsin increase resting renin in conscious rabbits and enhance the renin secretory response to beta-adrenergic stimulation. Milrinone also increases renin secretion in human subjects. The PDE4 inhibitors rolipram and Ro 20-1724 both increase renin secretion in rabbits and also enhance the renin response to beta-adrenergic stimulation. Studies in other laboratories have implicated other PDE families in the control of renin secretion. The aim of this review is to present current concepts concerning the PDEs and to discuss their role in the control of renin secretion by the kidneys.     

Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The feasibility of these enzymes as drug targets is exemplified by the commercial and clinical successes of the erectile dysfunction drugs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). PDE inhibitors are also currently available or in development for treatment of a variety of other pathological conditions. In this review the basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed. How these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered. PDEs hold great promise as drug targets and recent research advances make this an exciting time for the field of PDE research.