Novel marine-derived ligands for probing GluR function

用于探测 GluR 功能的新型海洋衍生配体

• 批准号: 8096612
• 负责人: GEOFFREY T SWANSON
• 金额: $ 28.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096612
• 关键词: AMPA Receptors; Affinity; Agonist; Amino Acids; Applications Grants; Basic Science; Binding; Biological; Brain; Chronic; Clinical Research; Cognition Disorders; Convulsants; Disease; Epilepsy; Family; Generations; Glutamate Receptor; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Investigation; Japan; Kainic Acid Receptors; Kinetics; Ligands; Marines; Mediator of activation protein; Migraine; Modification; Molecular; Molecular Conformation; Natural Products Chemistry; Neuraxis; Neurons; Pain; Physiological; Porifera; Preparation; Prevention; Process; Property; Publishing; Receptor Signaling; Recombinants; Research; Role; Screening procedure; Slice; Specificity; Stereoisomer; Structural Models; Structure; Synaptic Receptors; Synaptic Transmission; Synthesis Chemistry; Testing; Therapeutic Intervention; Therapeutic Uses; Treatment Efficacy; Work; analog; base; clinically relevant; design; dysiherbaine; insight; marine organism; nervous system disorder; novel; programs; receptor; research study; small molecule; structural biology; synergism; tool

DESCRIPTION (provided by applicant): The goal of this research effort is to identify new pharmacological agents that act on ionotropic glutamate receptors, the primary mediators of excitatory synaptic transmission in the mammalian brain. As well, we seek to understand how such molecules interact with the binding domains of their target receptors to generate selective pharmacological profiles. The research program is based on the premise that pharmacologically and clinically relevant neuroactive molecules can be isolated and characterized from marine sponges. We previously described the most potent seizurogenic amino acid yet characterized, dysiherbaine (DH), which was purified from a marine sponge extract. DH is a potent convulsant by virtue of its extremely high affinity for kainate receptors (KARs). Furthermore, small modifications of the DH structure switched its activity from that of a potent agonist to a selective antagonist, suggesting that DH could serve as template from which to generate selective KAR antagonists with unique pharmacological profiles. Such antagonists could be of relevance to both basic and clinical research, because few selective KAR antagonists have been identified and compounds with this pharmacological profile have potential therapeutic efficacy for treatment of pain and epilepsy. To pursue this goal we first will screen novel analogs of DH for activity as selective KAR antagonists. Preliminary results demonstrate that synthetic stereoisomers and other analogs of dysiherbaine have a variety of activities and affinity profiles on kainate receptors. Those antagonists with novel subunit-selectivity will be tested for activity on synaptic receptors in brain slice preparations. Second, we will carry out structure-function studies to test specific hypotheses regarding the molecular interactions between different KAR subunits and DH-related ligands. The results will inform the generation of new synthetic ligands designed to have particular pharmacological activities on KARs. Third, we will isolate and characterize the active principles in a bioactive sponge extract that potentiates AMPA and KAR currents. This activity is similar to that of AMPA receptor modulators currently under investigation for efficacy in prevention of cognitive decline. In summary, these projects have the shared goal of identification and pharmacological analysis of therapeutically promising molecules for treatment of neurological diseases.

描述(申请人提供)：这项研究的目标是寻找作用于哺乳动物大脑中兴奋性突触传递的主要媒介--离子型谷氨酸受体的新的药理制剂。此外，我们还试图了解这些分子如何与其目标受体的结合区域相互作用，以产生选择性的药理学特征。这项研究计划的前提是，可以从海绵中分离出具有药理和临床意义的神经活性分子，并对其进行表征。我们之前描述了迄今为止最有效的致痫氨基酸，Dysiherbaine(DH)，它是从海绵提取物中纯化出来的。由于它对海人酸受体(KARs)有极高的亲和力，因此是一种强效的惊厥剂。此外，对水解酶结构的微小修饰将其活性从有效的激动剂转变为选择性的拮抗剂，这表明水解酶可以作为模板来产生具有独特药理特征的选择性KAR拮抗剂。这些拮抗剂可能与基础和临床研究有关，因为几乎没有发现选择性的KAR拮抗剂，具有这种药理特征的化合物具有潜在的治疗疼痛和癫痫的疗效。为了实现这一目标，我们首先将筛选具有选择性KAR拮抗剂活性的新型类似物。初步结果表明，合成的立体异构体和其他类似物对海人藻酸受体具有不同的活性和亲和力。这些具有新的亚单位选择性的拮抗剂将在脑片准备中测试突触受体的活性。其次，我们将进行结构-功能研究，以检验关于不同KAR亚基与水解酶相关配体之间的分子相互作用的具体假设。这一结果将为新一代合成配体的产生提供信息，这些配体旨在对KARS具有特殊的药理活性。第三，我们将分离和鉴定生物活性海绵提取物中增强AMPA和KAR电流的活性成分。这一活性类似于目前正在研究的AMPA受体调节剂在预防认知衰退方面的有效性。总而言之，这些项目都有一个共同的目标，那就是识别和药理学分析治疗神经系统疾病的具有治疗前景的分子。

项目成果

Novel N-methylated 8-oxoisoguanines from Pacific sponges with diverse neuroactivities.

• DOI: 10.1021/jm100490m
• 发表时间: 2010-08-26
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Sakurada T;Gill MB;Frausto S;Copits B;Noguchi K;Shimamoto K;Swanson GT;Sakai R
• 通讯作者: Sakai R

Kainate receptors coming of age: milestones of two decades of research.

• DOI: 10.1016/j.tins.2010.12.002
• 发表时间: 2011-03
• 期刊: TRENDS IN NEUROSCIENCES
• 影响因子: 15.9
• 作者: Contractor, Anis;Mulle, Christophe;Swanson, Geoffrey T.
• 通讯作者: Swanson, Geoffrey T.

A combined bioinformatics and chemoinformatics approach for developing asymmetric bivalent AMPA receptor positive allosteric modulators as neuroprotective agents.

• DOI: 10.1002/cmdc.201200554
• 发表时间: 2013-02
• 期刊: CHEMMEDCHEM
• 影响因子: 3.4
• 作者: Chen, Haijun;Wang, Cheng Z.;Ding, Chunyong;Wild, Christopher;Copits, Bryan;Swanson, Geoffrey T.;Johnson, Kenneth M.;Zhou, Jia
• 通讯作者: Zhou, Jia

High-affinity kainate receptor subunits are necessary for ionotropic but not metabotropic signaling.

高亲和力的海藻酸盐受体亚基是离子型但不是代谢性信号传导所必需的。

• DOI: 10.1016/j.neuron.2009.08.010
• 发表时间: 2009-09-24
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Fernandes, Herman B.;Catches, Justin S.;Petralia, Ronald S.;Copits, Bryan A.;Xu, Jian;Russell, Theron A.;Swanson, Geoffrey T.;Contractor, Anis
• 通讯作者: Contractor, Anis

Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs.

• DOI: 10.1016/j.bmc.2010.04.044
• 发表时间: 2010-06-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Oikawa, Masato;Ikoma, Minoru;Sasaki, Makoto;Gill, Martin B.;Swanson, Geoffrey T.;Shimamoto, Keiko;Sakai, Ryuichi
• 通讯作者: Sakai, Ryuichi