Receptor-Specific Excitatory Amino Acid Analogues

受体特异性兴奋性氨基酸类似物

• 批准号: 7234301
• 负责人: A RICHARD CHAMBERLIN
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-20 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234301
• 关键词: Agonist; Area; Behavior; Biological; Biological Assay; Biological Factors; Class; Epilepsy; Excitatory Amino Acid Receptors; Excitatory Amino Acids; Fluorescence; Foundations; Glutamate Receptor; Glutamates; Grant; Impaired cognition; Individual; Institutes; Intention; Kainic Acid; Laboratories; Lead; Libraries; Ligands; Modification; Mono-S; N-Methylaspartate; Neurodegenerative Disorders; Neurons; Numbers; Oocytes; Pain; Physiological; Process; Property; Pyrrolidines; Range; Screening procedure; Stroke; Structure; System; Technology; Testing; Therapeutic; Therapeutic Agents; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; analog; base; desensitization; dicarboxylate; dysiherbaine; excitotoxicity; expectation; high throughput screening; interest; kainate; kaitocephalin; member; molecular modeling; neuroprotection; novel; professor; pyrrolidine; receptor; small molecule; uptake

DESCRIPTION (provided by applicant): This competing renewal will build on the foundation laid during the previous two 4-year grant periods in developing new small molecule ligands for excitatory amino acid (EAA) receptors and transporters. Our intention is to tightly focus our continued efforts on a problem that presents one of the next major challenges in this field, namely the pharmacological differentiation of EAA receptor subtypes that comprise the respective major ionotropic receptor classes, specifically AMPA (comprised of subtypes iGluR1-5), Kainate (subtypes iGluR5-7, KA-1, and KA-2), and NMDA (subtypes NR1-3). We have developed synthesis technology for preparing several structural classes of glutamate analogues (pyrrolidine dicarboxylates, kainates, dysiherbaines, and kaitocephalins) known to be active agonists or antagonists; however, by and large the action of such compounds within the receptor subtypes has yet to be delineated. This is a very important issue because individual members of these subtype groups have been implicated in a growing number of therapeutic areas, including stroke and neurodegenerative diseases, cognitive impairment, epilepsy, and pain. As a result, there is a great deal of interest in the discovery of subtype-selective agonists and antagonists as possible leads for therapeutic agents. We will focus our efforts on these "proven" groups of glutamate ligands, with the expectation that structural modifications will in some cases lead to new compounds with modified subtype selectivities or other novel activities. To accelerate the discovery process, a library approach based on these structural types will be instituted. Because a given pharmacological property (e.g., excitotoxicity) can be a consequence of multiple factors (e.g., subtype-specific agonist potency, desensitization behavior, transport behavior, etc.), the biological screening of new compounds should be as broad as practical. We have therefore teamed up with four outstanding laboratories to screen our analogues and libraries in a wide range of assays: Professor Olivier Civelli (high throughput screening of receptor subtypes for agonist/antagonist activity), Ricardo Miledi (detailed analysis of active compounds in oocyte assays), Professor Gary Lynch (neuronal assays), and Professor Richard Bridges (transport, excitotoxicity, and neuroprotection assays).

描述（由申请人提供）：这一竞争性更新将建立在前两个4年资助期为兴奋性氨基酸（EAA）受体和转运蛋白开发新的小分子配体的基础上。我们的目的是将我们的持续努力紧密地集中在该领域的下一个主要挑战之一的问题上，即EAA受体亚型的药理学分化，所述EAA受体亚型包括相应的主要离子型受体类别，特别是AMPA（由亚型iGluR 1 -5组成）、红藻氨酸盐（Kainate）（亚型iGluR 5 -7、KA-1和KA-2）和NMDA（亚型NR 1 -3）。我们已经开发了用于制备已知为活性激动剂或拮抗剂的几种结构类别的谷氨酸类似物（吡咯烷二羧酸盐、红藻氨酸盐、dysiherbaines和kaitocephalins）的合成技术;然而，大体上这些化合物在受体亚型内的作用尚未被描绘。这是一个非常重要的问题，因为这些亚型组的个体成员已涉及越来越多的治疗领域，包括中风和神经退行性疾病，认知障碍，癫痫和疼痛。因此，在发现亚型选择性激动剂和拮抗剂作为治疗剂的可能先导物方面存在很大的兴趣。 我们将把我们的努力集中在这些“已证实”的谷氨酸配体组上，期望结构修饰在某些情况下会导致具有修饰的亚型选择性或其他新活性的新化合物。为了加速发现过程，将建立基于这些结构类型的库方法。因为给定的药理学性质（例如，兴奋性毒性）可以是多种因素的结果（例如，亚型特异性激动剂效力、脱敏行为、转运行为等），新化合物的生物筛选应尽可能广泛。因此，我们与四个杰出的实验室合作，在广泛的试验中筛选我们的类似物和文库：Olivier Civelli教授（激动剂/拮抗剂活性的受体亚型的高通量筛选），Ricardo Miledi（卵母细胞试验中活性化合物的详细分析），加里林奇教授（神经元试验）和Richard Bridges教授（运输，兴奋毒性和神经保护试验）。

项目成果

A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate.

前脑突触体中钠依赖性谷氨酸转运蛋白的构象限制竞争性抑制剂：L-抗内-3,4-甲基吡咯烷二羧酸酯。

• DOI: 10.1016/0304-3940(94)90019-1
• 发表时间: 1994
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Bridges,RJ;Lovering,FE;Koch,H;Cotman,CW;Chamberlin,AR
• 通讯作者: Chamberlin,AR

Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin.

• DOI: 10.1016/j.bmcl.2008.11.004
• 发表时间: 2006-04
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: R. Vaswani;A. Limon;J. M. Reyes-Ruiz;R. Miledi;A. Chamberlin

A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system.

• DOI: 10.1002/chin.199929281
• 发表时间: 1999-05
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: R. Bridges;M. Kavanaugh;A. Chamberlin

Differing effects of substrate and non-substrate transport inhibitors on glutamate uptake reversal.

底物和非底物转运抑制剂对谷氨酸摄取逆转的不同影响。

• DOI: 10.1046/j.1471-4159.2001.00668.x
• 发表时间: 2001
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Anderson,CM;Bridges,RJ;Chamberlin,AR;Shimamoto,K;Yasuda-Kamatani,Y;Swanson,RA
• 通讯作者: Swanson,RA

Diastereoselective synthesis of glutamate-appended oxolane rings: synthesis of (s)-(+)-lycoperdic acid.

谷氨酸附加的四氢呋喃环的非对映选择性合成：(s)-( )-番茄酸的合成。

• DOI: 10.1021/jo7017137
• 发表时间: 2007
• 期刊: The Journal of organic chemistry
• 作者: Cohen,JamieL;Chamberlin,ARichard
• 通讯作者: Chamberlin,ARichard