The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.

2018-04-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Targeting Glycine Reuptake in Alcohol Seeking and Relapse

3区 · 医学

Article

作者: Spanagel, Rainer ; Bespalov, Anton ; Behl, Berthold ; Takahashi, Tatiane T ; Alberati, Daniela ; Vengeliene, Valentina ; Roßmanith, Martin

It has recently been demonstrated that pharmacological blockade of the glycine transporter 1 (GlyT1) reduced alcohol intake and relapse in rats. The aim of the present study was to further explore the role of GlyT1 in alcohol relapse-like behavior. For this purpose we used three different GlyT1 blockers-SSR504734, A-1246399, and RO4993850-and tested their effect on alcohol-seeking and relapse-like consumption. Two behavioral models, the alcohol deprivation effect model and the cue-induced reinstatement model, were used. Our data show that all three GlyT1 blockers reduce relapse-like alcohol consumption and cause either minimal or no side effects, measured as changes in home-cage activity, water intake, and body weight. In the reinstatement test, GlyT1 blockers completely abolished alcohol-seeking responses. Furthermore, we tested other drug/cue associations and found that cocaine-seeking responses were also abolished by GlyT1 blockade. Our data confirm that GlyT1 can be used as a target to develop novel anticraving and antirelapse drugs.

2016-01-01·CHEMICAL & PHARMACEUTICAL BULLETIN4区 · 医学

Discovery of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a Potent Glycine Transporter 1 Inhibitor

4区 · 医学

Article

作者: Aoki, Takeshi ; Shibata, Tsuyoshi ; Oda, Koji ; Abe, Kumi ; Kawamoto, Hiroshi ; Yamamoto, Shuji ; Kawakita, Yasunori

A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemotypes to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (2, SSR504734), the introduction of heteroaromatic rings enabled an increase in the GlyT1 inhibitory activity. Subsequent optimization led to the identification of 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (7w), which showed a powerful GlyT1 inhibitory activity (IC50=1.8 nM), good plasma exposure and a plasma to brain penetration in rats that was sufficient to evaluate the compound's pharmacological properties. Compound 7w showed significant effects in several rodent models for schizophrenia without causing any undesirable central nervous system side effects.

项与 SSR-504734 相关的新闻（医药）

2024-03-21

·生物探索

Cell | 中国科学院赵岩团队揭示甘氨酸转运蛋白GlyT1的底物识别和抗精神分裂药物抑制机制

引言甘氨酸转运蛋白1 (GlyT1)通过清除突触间隙中的甘氨酸，在抑制性和兴奋性神经传递的调节中起着至关重要的作用。鉴于其与谷氨酸/甘氨酸共激活的NMDA受体(NMDARs)密切相关，GlyT1已成为治疗精神分裂症的中心靶点，精神分裂症通常与功能低下的NMDARs有关。2024年3月20日，中国科学院生物物理研究所赵岩团队在Cell 在线发表题为“Transport mechanism and pharmacology of the human GlyT1”的研究论文，该研究报道了GlyT1与底物甘氨酸和药物ALX-5407, SSR504734和PF-03463275结合的冷冻电镜结构。这些结构在转运循环的三种基本状态下被捕获—向外、封闭和内向—使得能够阐明与甘氨酸再摄取相关的构象变化的全面蓝图。此外，还确定了三个特定的容纳药物的口袋，为其抑制机制和选择性的结构基础提供了清晰的见解。总的来说，这些结构对底物和抗精神分裂症药物的转运机制和识别提供了重要的见解，从而为设计治疗精神分裂症的小分子提供了一个平台。甘氨酸是一种重要的神经递质，在中枢神经系统(CNS)中发挥多种功能。作为一种抑制性神经递质，它主要活跃于脑干和脊髓，在那里它参与了广泛的运动和感觉功能。然而，它也作为NMDA受体(NMDARs)的强制性共激动剂参与兴奋性神经传递甘氨酸的突触浓度主要受两种高亲和的钠和氯依赖性转运蛋白调节，甘氨酸转运蛋白1 (GlyT1) (SLC6A9) 和GlyT2 (SLC6A5) ，它们属于神经递质钠同向转运蛋白(NSS)家族这两种转运蛋白在神经系统中具有互补的分布和功能。与主要表达于甘氨酸神经末梢的GlyT2不同，GlyT1主要表达于星形胶质细胞和谷氨酸神经元中，并被认为通过影响协同激动剂甘氨酸的可用性来调节NMDARs的活性。GlyT1纯合子敲除小鼠会出现严重的神经运动缺陷，导致过早死亡，而GlyT1+/-杂合子小鼠，GlyT1水平降低50%，谷氨酸能功能受损，突出了GlyT1在抑制性和兴奋性神经传递中的关键功能作用。精神分裂症是一种严重的慢性精神疾病，患病率高达1%越来越多的证据表明NMDAR在精神分裂症的病理生理中起着关键作用。值得注意的是，NMDARs的开放通道阻滞剂可以在健康个体中诱导精神分裂症样症状。因此，增强NMDARs的功能已成为治疗精神分裂症的一种有前景的治疗策略。临床研究表明，NMDAR中甘氨酸位点的激动剂，如甘氨酸和D-丝氨酸，可能对治疗精神分裂症有益。因此，许多选择性GlyT1抑制剂被开发出来，旨在提高突触间隙中的甘氨酸浓度，间接增强NMDARs的活性。根据其化学结构，这些GlyT1选择性抑制剂可分为基于肌氨酸和非基于肌氨酸的抑制剂。肌氨酸是GlyT1的内源性抑制剂，不影响GlyT2。肌氨酸的衍生物，如ALX-5407可有效抑制GlyT1，特异性高。然而，基于肌氨酸的抑制剂的抑制作用往往是不可逆的，并导致严重的副作用。模式图（Credit: Cell）为了避免这一问题，已经开发了各种非肌氨酸衍生物抑制剂，包括以SSR504734为代表的甲基苯甲酸酯衍生GlyT1抑制剂，以PF-03463275为代表的杂芳酰胺GlyT1抑制剂，这些类别的药物目前正在进行上市前临床试验。尽管GlyT1与Cmpd1结合的晶体结构已经确定，但它只揭示了一个面向内的构象，还有许多机制有待阐明。其中包括底物甘氨酸识别、离子结合和转运周期中的构象变化的分子机制，这对于理解大脑中甘氨酸再摄取过程至关重要。此外，探索各种化学衍生物如何选择性地结合和抑制GlyT1是至关重要的，这对于进一步合理设计有效的、高度特异性的、可逆的GlyT1抑制剂来治疗精神分裂症至关重要。该研究确定了GlyT1结合底物甘氨酸(GlyT1Gly)、肌氨酸基抑制剂ALX-5407 (GlyT1ALX)、非肌氨酸基抑制剂SSR504734 (GlyT1SSR)和PF03463275 (GlyT1PF)的结构。这些结构稳定在三种不同的构象中，包括外向构象(GlyT1SSR/GlyT1PF)，封闭状态(GlyT1Gly)和内向构象(GlyT1ALX)。此外，借助[3h]甘氨酸摄取测定，能够清楚地证明特定的结构差异，使每种抑制剂能够区分GlyT1和GlyT2。该研究阐明了底物结合、构象变化的分子基础，以及抗精神分裂症药物的变构或竞争、可逆或不可逆结合模式，以及它们的选择性，为合理设计针对不同构象的强效、选择性和可逆药物提供了平台，从而为精神分裂症的治疗干预提供了潜在的治疗手段。原文链接https://www.cell.com/cell/abstract/S0092-8674(24)00228-9责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

100 项与 SSR-504734 相关的药物交易

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