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ACKNOWLEDGMENT OF REVIEWERS 审稿人致谢
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.00028.x
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引用次数: 0
Cortagine: Behavioral and Autonomic Function of the Selective CRF Receptor Subtype 1 Agonist 选择性CRF受体亚型1激动剂的行为和自主神经功能
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.00027.x
Catherine Borna Farrokhi, Philip Tovote, Robert J. Blanchard, D. Caroline Blanchard, Yoav Litvin, Joachim Spiess

Corticotropin-releasing factor (CRF) is a neuropeptide and mediating component of neuroendocrine, autonomic, and behavioral processes associated with the stress response. The two receptor subtypes identified in the mammalian brain, CRF receptor subtype 1 (CRF1) and CRF2, are suggested to differentially modulate these processes. Manipulation of these receptors with selective CRF compounds and transgenic models has revealed, in most studies, a clear potentiation of the stress response through central activation of CRF1. However, pharmacological activation of CRF restricted to CRF1 has been limited by the availability of selective peptidic compounds. Recently, a highly selective CRF1 agonist, cortagine, has been developed. It was synthesized from chimeric intermediate sequences of ovine CRF, sauvagine, and human/rat CRF into a highly soluble peptide with strong affinity for CRF1 (IC50 < 5 nM) and a very low binding preference for CRF2 (IC50 > 500 nM). Affinity for the CRF binding protein (IC50 > 1,000nM) can be abolished by the addition of a glutamate residue on position 21 of the cortagine peptide sequence. Cortagine has recently been tested in a variety of preclinical models of behavior including the elevated-plus-maze (EPM), forced swim test (FST), homecage, and rat exposure test (RET). Preliminary characterization in the EPM and FST suggested that this compound elicits anxiogenic and antidepressant-like effects, respectively. Additional testing in the homecage and RET, which targets various elements of behavior, directs to a more potent anxiogenic profile of cortagine. In this review, we discuss the behavioral findings and the tests used to measure these effects. Finally, we also discuss preliminary findings of autonomic activation obtained by central injection of cortagine that support CRF1 involvement in the modulation of heart rate and heart rate variability.

促肾上腺皮质激素释放因子(CRF)是一种神经肽,介导与应激反应相关的神经内分泌、自主神经和行为过程。在哺乳动物大脑中发现的两种受体亚型,CRF受体亚型1 (CRF1)和CRF2,被认为对这些过程有差异调节。在大多数研究中,用选择性CRF化合物和转基因模型操纵这些受体表明,通过CRF1的中枢激活可以明显增强应激反应。然而,仅限于CRF1的CRF的药理激活受到选择性肽化合物的可用性的限制。最近,一种高选择性的CRF1激动剂cortagine被开发出来。它是由绵羊CRF、山羊CRF和人/大鼠CRF的中间序列嵌合合成的,是一种与CRF1亲和力强的高可溶性肽(IC50 <5 nM),对CRF2的结合偏好非常低(IC50 >500海里)。对CRF结合蛋白的亲和力(IC50 >1,000nM)可以通过在cortagine肽序列的第21位添加谷氨酸残基来消除。Cortagine最近在多种临床前行为模型中进行了测试,包括抬高+迷宫(EPM)、强迫游泳试验(FST)、家养和大鼠暴露试验(RET)。EPM和FST的初步表征表明,该化合物分别引起焦虑和抗抑郁样作用。在家庭和RET中进行的额外测试,针对行为的各种因素,指向了更有效的cortagine焦虑性特征。在这篇综述中,我们讨论了行为的发现和用于测量这些影响的测试。最后,我们还讨论了通过中央注射cortagine获得的自主神经激活的初步发现,这些发现支持CRF1参与心率和心率变异性的调节。
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引用次数: 26
Guanfacine and Guanfacine Extended Release: Treatment for ADHD and Related Disorders 胍法辛和胍法辛缓释:治疗ADHD及相关疾病
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.00026.x
David J. Posey, Christopher J. McDougle

Guanfacine, an α2A adrenoceptor agonist, is U.S. Food and Drug Administration (FDA)–approved for the treatment of hypertension in adolescents and adults. It also has been used "off-label" for several years in children as a possible treatment for attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDDs). Small placebo-controlled trials support the use of guanfacine for the treatment of ADHD. There is more limited research on the use of guanfacine in treating hyperactivity occurring in children diagnosed with PDD. Recently, guanfacine extended release (GXR), a once-daily formulation has been manufactured and studied in phase III clinical trials. Based on preliminary scientific presentations, it also appears to be efficacious in improving ADHD in children. The most common adverse effects associated with guanfacine and GXR treatment is sedation. Adverse cardiovascular effects are uncommon, although modest reductions in blood pressure and heart rate are common. If GXR is FDA-approved, it would be the first α2A adrenoceptor agonist marketed for ADHD.

胍法辛是一种α2A肾上腺素受体激动剂,已被美国食品和药物管理局(FDA)批准用于治疗青少年和成人高血压。几年来,它也被“标签外”用于儿童,作为注意力缺陷/多动障碍(ADHD)和广泛性发育障碍(pdd)的可能治疗方法。小型安慰剂对照试验支持使用胍法辛治疗多动症。使用胍法辛治疗诊断为PDD的儿童多动症的研究更为有限。最近,每日一次的胍法辛缓释片(GXR)已被生产并进入III期临床试验。根据初步的科学报告,它似乎对改善儿童多动症也有效。与胍法辛和GXR治疗相关的最常见不良反应是镇静。虽然血压和心率的适度降低很常见,但对心血管的不良影响并不常见。如果GXR获得fda批准,它将成为上市治疗ADHD的第一种α2A肾上腺素受体激动剂。
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引用次数: 27
AUTHOR INDEX FOR VOLUME 13 第13卷的作者索引
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.auindex_1.x
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引用次数: 0
Pharmacology of the β-Carboline FG-7142, a Partial Inverse Agonist at the Benzodiazepine Allosteric Site of the GABAA Receptor: Neurochemical, Neurophysiological, and Behavioral Effects GABAA受体苯二氮卓类变构部位的部分逆激动剂β-卡波林FG-7142的药理学:神经化学、神经生理和行为效应
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.00025.x
Andrew K. Evans, Christopher A. Lowry

Given the well-established role of benzodiazepines in treating anxiety disorders, β-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABAA receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the α1 subunit-containing GABAA receptor, although it is not selective. FG-7142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the α1 subunit-containing GABAA receptor. FG-7142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and β-carboline agonists, and increase the effectiveness of subsequent GABAA receptor antagonists and β-carboline inverse agonists. FG-7142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABAA receptor subtypes involved in specific behavioral and physiological responses.

鉴于苯二氮卓类药物在治疗焦虑障碍中的作用,β-碳胺类药物在GABAA受体苯二氮卓变构部位的作用范围从完全激动剂到完全逆激动剂,可以为焦虑相关生理和行为的神经机制提供有价值的见解。FG-7142是苯二氮卓类变构部位的部分逆激动剂,对含α1亚基的GABAA受体具有最高的亲和力,尽管它没有选择性。FG-7142在含α1亚基GABAA受体介导的gaba诱导的氯通量调节中也具有最高的效果。FG-7142激活已知的焦虑相关神经网络,并与该网络中的血清素能、多巴胺能、胆碱能和去甲肾上腺素能调节系统相互作用。FG-7142在包括人类在内的许多哺乳动物和非哺乳动物物种的各种实验范式中已被证明可诱导焦虑相关的行为和生理反应。FG-7142在焦虑相关的行为范式中具有促进冲突的作用,调节注意过程,并增加心加速交感反应性和神经内分泌反应性。急性和慢性FG-7142治疗均具有惊厥前作用,上调皮质肾上腺素受体,降低GABA和β-卡伯碱激动剂的后续作用,并增加后续GABAA受体拮抗剂和β-卡伯碱逆激动剂的有效性。FG-7142作为一种部分逆激动剂,可以帮助阐明苯二氮卓类药物结合位点完全激动作用的个体成分,并可能用于识别参与特定行为和生理反应的特定GABAA受体亚型。
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引用次数: 82
SUBJECT INDEX FOR VOLUME 13 第13卷的主题索引
Pub Date : 2007-12-07 DOI: 10.1111/j.1527-3458.2007.suindex_1.x
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引用次数: 0
Ginsenosides: Are Any of them Candidates for Drugs Acting on the Central Nervous System? 人参皂苷:它们是中枢神经系统药物的候选药物吗?
Pub Date : 2007-11-13 DOI: 10.1111/j.1527-3458.2007.00023.x
Seung-Yeol Nah, Dong-Hyun Kim, Hyewhon Rhim

The last two decades have shown a marked expansion in the number of publications regarding the effects of Panax ginseng. Ginsenosides, which are unique saponins isolated from Panax ginseng, are the pharmacologically active ingredients in ginseng, responsible for its effects on the central nervous system (CNS) and the peripheral nervous system. Recent studies have shown that ginsenosides regulate various types of ion channels, such as voltage-dependent and ligand-gated ion channels, in neuronal and heterologously expressed cells. Ginsenosides inhibit voltage-dependent Ca2+, K+, and Na+ channel activities in a stereospecific manner. Ginsenosides also inhibit ligand-gated ion channels such as N-methyl-d-aspartate, some subtypes of nicotinic acetylcholine, and 5-hydroxytryptamine type 3 receptors. Competition and site-directed mutagenesis experiments revealed that ginsenosides interact with ligand-binding sites or channel pore sites and inhibit open states of ion channels. This review will introduce recent findings and advances on ginsenoside-induced regulation of ion channel activities in the CNS, and will further expand the possibilities that ginsenosides may be useful and potentially therapeutic choices in the treatment of neurodegenerative disorders.

在过去的二十年中,关于人参作用的出版物数量显著增加。人参皂苷是从人参中分离出来的一种独特的皂苷类物质,是人参中具有药理活性的成分,对中枢神经系统和外周神经系统具有重要作用。最近的研究表明,人参皂苷在神经元和异源表达细胞中调节多种类型的离子通道,如电压依赖性和配体门控离子通道。人参皂苷以立体特异性的方式抑制电压依赖性Ca2+, K+和Na+通道活性。人参皂苷还抑制配体门控离子通道,如n -甲基-d-天冬氨酸、某些亚型烟碱乙酰胆碱和5-羟色胺3型受体。竞争和定点诱变实验表明,人参皂苷与配体结合位点或通道孔位点相互作用,抑制离子通道的开放状态。本文将介绍人参皂苷诱导的中枢神经系统离子通道活性调控的最新发现和进展,并将进一步扩大人参皂苷在神经退行性疾病治疗中的潜在治疗选择的可能性。
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引用次数: 169
TDIQ (5,6,7,8–tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): Discovery, Pharmacological Effects, and Therapeutic Potential TDIQ(5,6,7,8 -四氢-1,3-二恶罗[4,5-g]异喹啉):发现、药理作用和治疗潜力
Pub Date : 2007-11-13 DOI: 10.1111/j.1527-3458.2007.00022.x
Richard Young

Chemically, TDIQ (5,6,7,8–tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) can be viewed as a conformationally restricted phenylalkylamine that is related in structure to amphetamine but does not stimulate (or depress) locomotor activity in rodents. In radioligand binding studies TDIQ displays selective affinity for α2-adrenergic receptor subsites (i.e., α2A-, α2B-, and α2C-adrenergic receptors), and behavioral data suggest that it might exert an agonist (or partial agonist) effect at α2-adrenergic receptors or interact at α2-adrenergic heteroreceptors. Drug discrimination studies in rats indicate that TDIQ: (1) serves as a discriminative stimulus, (2) may be useful in the treatment of symptoms associated with the abuse of cocaine, and (3) exhibits a low potential for abuse. In addition, TDIQ exhibits a dose-dependent and wide dissociation between doses that produce an anxiolytic-like effect or an inhibition of “snack” consumption in mice and doses that produce minimal, if any, effects in tests that measure a potential for disruption of coordinated movement or motor activity. Also, TDIQ displays negligible effects on the heart rate (HR) and blood pressure (BP) of mice. Taken together, the preclinical data suggest that TDIQ exhibits a favorable ratio of therapeutic-like effects (anxiolytic, therapeutic adjunct in the treatment of cocaine abuse, and appetite suppression) to side effect-like activities (behavioral impairment, drug abuse, or adverse cardiovascular effect). As such, TDIQ could: (1) be a forerunner for a new type of chemical entity in the treatment of certain forms of anxiety and/or obesity and (2) serve as a structural template in the discovery and development of additional agents that might be selective for α2-adrenergic receptors.

化学上,TDIQ(5,6,7,8 -四氢-1,3-二恶唑[4,5-g]异喹啉)可以被视为构象受限的苯烷基胺,结构上与安非他明相关,但不会刺激(或抑制)啮齿动物的运动活动。在放射性配体结合研究中,TDIQ对α2-肾上腺素能受体亚位(即α2A-、α2B-和α 2c -肾上腺素能受体)表现出选择性亲和力,行为数据表明它可能对α2-肾上腺素能受体发挥激动剂(或部分激动剂)作用,或与α2-肾上腺素能异受体相互作用。在大鼠身上进行的药物鉴别研究表明,TDIQ:(1)可作为一种鉴别刺激,(2)可能有助于治疗与可卡因滥用有关的症状,(3)显示出较低的滥用可能性。此外,TDIQ在产生抗焦虑作用或抑制小鼠“零食”消耗的剂量和在测量协调运动或运动活动的潜在破坏的测试中产生最小(如果有的话)影响的剂量之间表现出剂量依赖性和广泛的分离。此外,TDIQ对小鼠心率(HR)和血压(BP)的影响微不足道。综上所述,临床前数据表明,TDIQ表现出良好的治疗样效果(抗焦虑,治疗可卡因滥用的辅助治疗和食欲抑制)与副作用样活动(行为障碍,药物滥用或不良心血管作用)的比例。因此,TDIQ可以:(1)成为治疗某些形式的焦虑和/或肥胖的新型化学实体的先驱;(2)作为发现和开发可能选择性α2-肾上腺素能受体的其他药物的结构模板。
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引用次数: 1
The Preclinical Properties of a Novel Group II Metabotropic Glutamate Receptor Agonist LY379268 新型II组代谢性谷氨酸受体激动剂LY379268的临床前特性
Pub Date : 2007-11-13 DOI: 10.1111/j.1527-3458.2007.00024.x
Gabor Imre

Activation of group II metabotropic glutamate (mGlu2/3) receptors reduces excessive glutamate release that is often associated with neurodegenerative and psychiatric disorders. This finding encouraged the search for potent and selective agonists as potential therapeutic agents. The search led to the discovery of LY379268 {(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid}, which is a highly potent and systemically available mGlu2/3 receptor agonist. LY379268 was effective in several animal models of stroke, epilepsy, drug abuse, schizophrenia, and pain. Suppression of motor activity is the major side effect of LY379268. Upon repeated administration tolerance develops to this side effect, while the therapeutic effects of LY379268 remain. To date, no clinical data with LY379268 are available. This review article summarizes the preclinical pharmacology of LY379268.

II组代谢型谷氨酸(mGlu2/3)受体的激活可减少谷氨酸的过度释放,而谷氨酸的过度释放通常与神经退行性疾病和精神疾病有关。这一发现鼓励寻找强效和选择性激动剂作为潜在的治疗剂。这项研究发现了LY379268 {(-)-2-oxa-4-氨基双环己烷-4,6-二羧酸},这是一种高效且全身可用的mGlu2/3受体激动剂。LY379268对中风、癫痫、药物滥用、精神分裂症和疼痛等动物模型均有效。抑制运动活动是LY379268的主要副作用。反复给药后,对该副作用产生耐受性,而LY379268的治疗效果仍然存在。迄今为止,尚无LY379268的临床数据。本文就LY379268的临床前药理作用进行综述。
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引用次数: 93
Catechol-O-methyltransferase and Its Inhibitors in Parkinson's Disease 儿茶酚- o -甲基转移酶及其抑制剂在帕金森病中的作用
Pub Date : 2007-09-24 DOI: 10.1111/j.1527-3458.2007.00020.x
Maria João Bonifácio, P. Nuno Palma, Luís Almeida, Patrício Soares-da-Silva

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the dopamine replacement therapy with levodopa together with an inhibitor of aromatic amino acid decarboxylase (AADC). The efficacy of this therapy, however, decreases with time and most patients develop fluctuating responses and dyskinesias. The last decade showed that the use of catechol-O-methyltransferase inhibitors as adjuvants to the levodopa/AADC inhibitor therapy, significantly improves the clinical benefits of this therapy.

The purpose of this article is to review the current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.

帕金森病(PD)是一种以多巴胺能神经元退化为特征的神经系统疾病,纹状体多巴胺水平降低导致特征性运动症状。目前最有效的治疗方法仍然是左旋多巴与芳香氨基酸脱羧酶(AADC)抑制剂联合使用多巴胺替代疗法。然而,这种疗法的疗效随着时间的推移而降低,大多数患者出现波动反应和运动障碍。过去十年表明,使用儿茶酚- o -甲基转移酶抑制剂作为左旋多巴/AADC抑制剂治疗的佐剂,显著提高了该治疗的临床疗效。本文的目的是综述目前关于儿茶酚- o -甲基转移酶(COMT)的知识和COMT抑制剂在PD中的作用,COMT抑制剂作为PD的一种新的治疗方法,涉及左旋多巴在大脑靶区转化为多巴胺,并促进该胺在受体位点的持续作用。本文对COMT抑制剂的发现和发展进行了历史回顾,特别强调了目前正在临床开发的内比卡彭,以及已被批准作为PD治疗辅助药物的恩他卡彭和托尔卡彭。本文综述了这些药物的人体药代动力学和药效学特性,以及它们的临床疗效和安全性。
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引用次数: 174
期刊
CNS drug reviews
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