Access to a Saxitoxin-like Library for Binding Studies of Na Voltage Channels

访问类石房蛤毒素库进行 Na 电压通道的结合研究

• 批准号: 9215525
• 负责人: Nicholas A. Isley
• 金额: $ 5.67万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215525
• 关键词: Affect; Analgesics; Architecture; Binding; Biology; Chemicals; Chemistry; Communities; Complex; Crystallization; Cyclization; Data; Development; Drug Design; Future; Generations; Guanidines; Health; Human; In Situ; Integral Membrane Protein; Ion Channel; Libraries; Link; Mammals; Metals; Methods; Molecular Probes; Neurotoxins; Pain; Pain management; Pattern; Play; Population; Property; Proteins; Research; Role; Route; Saxitoxin; Sodium; Structure; Structure-Activity Relationship; Therapeutic; Transition Elements; chronic pain; design; diazo compound; drug development; guanidinium; improved; interest; neurotoxic; propadiene; public health relevance; scaffold; small molecule; small molecule libraries; tool; voltage

 DESCRIPTION (provided by applicant): Development of a Lewis acidic transition-metal promoted cyclization of a bis-guanidinium allenyl unit leading toward tricyclic cores resembling saxitoxin will be undertaken. This will probe the reactivity profile of an otherwise unknown bis-guanidinium substituted allene insofar as its reactivity towards cyclizations is concerned. A modular approach is presented that allows for access to various substitution patterns and ring-sizes closely resembling saxitoxin for further structure-activity relationship (SAR) studies agains human sodium voltage (NaV) channels. Subtypes of these NaV channels have been linked to the mechanism of pain, which has sparked heavy interest in analgesic drug development. The lack of crystal structure data for the transmembrane proteins, however, hinders rational drug design. Such SAR studies with unnatural derivatives of saxitoxin against these channels are extremely limited or unknown and would help to elucidate the architecture of these proteins for future therapeutics. Current estimates conclude that ~30% of the U.S. population is afflicted with chronic pain; therefore, further understanding of these transmembrane proteins is paramount. Completion of the proposed research will achieve the following: 1) A better understanding of the reactivity profile in C−N bond construction of an allene unit using guanidine as nucleophiles; 2) Access to a metal carbenoid species in situ which has broad synthetic utility in the chemistry community, an alternative route that avoids potentially explosive diazo compounds; 3) Potential platform to access bis-guanidinium tricyclic cores with various ring-sizes and substitution patterns; 4) Correlate structure-activity relationships of saxitoxin-like scaffolds against the human NaV1.7 ion channel aiding in their structural elucidation for future rational design in analgesics of therapeutic value.

 描述（由申请人提供）：将开发一种刘易斯酸性过渡金属促进的双胍联烯基单元环化，形成类似石房蛤毒素的三环核心。就其对环化的反应性而言，这将探测未知的双胍取代的联烯的反应性特征。提出了一种模块化的方法，允许访问各种替代模式和环的大小非常类似石房蛤毒素的进一步结构-活性关系（SAR）的研究agains人类钠电压（NaV）通道。这些NaV通道的亚型与疼痛机制有关，这引发了人们对镇痛药物开发的浓厚兴趣。然而，缺乏跨膜蛋白的晶体结构数据，阻碍了合理的药物设计。用石房蛤毒素的非天然衍生物对这些通道的这种SAR研究是极其有限的或未知的，并且将有助于阐明这些蛋白质的结构以用于未来的治疗。目前的估计得出的结论是，约30%的美国人口患有慢性疼痛;因此，进一步了解这些跨膜蛋白是至关重要的。 完成这项研究将实现以下目标：1）更好地理解使用胍作为亲核试剂的丙二烯单元的C-N键构建反应性概况; 2） 原位获得在化学界具有广泛合成用途的金属类卡宾物质，这是避免潜在爆炸性重氮化合物的替代途径; 3）获得具有各种环尺寸和取代模式的双胍盐三环核的潜在平台; 4）石房蛤毒素的相关构效关系类似于抗人NaV1.7离子通道的支架，有助于它们的结构阐明，用于将来合理设计具有治疗价值的镇痛剂。