MOLECULAR MODELING, DESIGN AND EVALUATION OF BDZ LIGANDS

BDZ 配体的分子建模、设计和评估

• 批准号: 2118623
• 负责人: GILDA H LOEW
• 金额: $ 29.07万
• 依托单位: MOLECULAR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2118623
• 关键词: MOLECULAR; MODELING; DESIGN; EVALUATION; BDZ

The overall goal of this proposed interdisciplinary effort continues to be the computer assisted design of new therapeutic agents with improved pharmacological profiles, which exert their effects by binding to the BDZ/GABA-A receptor (BDZR ligands). To this end, we shall continue to 1) validate current hypotheses for non selective ligands involving common molecular determinants of recognition of BDZ/GABA-A receptor(s) and determinants of activation based on their anticonvulsant endpoint and identify promising medications designed using them. This goal will be accomplished by: a) Continued theoretical characterization of additional families of compounds reported in the literature that were not included in the original data set for hypothesis development, and b) synthesis and pharmacological evaluation of two of the families with predicted pharmacological profiles originally proposed based on this hypothesis: i) azaindoles; ii) pyrroloquinolines. 2) Enhance knowledge of BDZ in vitro and in vivo pharmacology in light of emerging developments in molecular biology, in a manner that will also result in an appropriate database for hypothesis refinement and design of second generation analogs. To accomplish this aim we shall: a) Synthesize analogs of compounds that have been reported to have interesting pharmacological profiles that could be useful to i) probe receptor heterogeneity because of their ability to bind selectively or ii) elicit qualitatively different responses i.e. agonism, antagonism, inverse agonism or no response in different behavioral endpoints, b) Continue to characterize receptor heterogeneity, addressing the question of the number of central BDZR subtypes using different brain regions reported to have limited subtype heterogeneity and using additional ligands; c) Explore the usefulness of chloride ion flux as an indication of agonist, antagonist and inverse agonist activity in each brain region used for receptor binding studies; d) Use the six in vivo endpoints: anxiolytic, anticonvulsant, hyperphagia, sedation, muscle relaxant and hypothermia, to characterize additional known families and the newly synthesized ones, found to bind with significant affinity to any BDZ/GABA-A receptor subtype. The goal of these studies is to determine promising differences in the ability of a set of chosen compounds to differentially elicit these activities. These results will be useful for two different purposes: i) to serve as a database for the design of activity-specific analogs and ii) to further elucidate the relationship between recognition of a given subtype and in vivo responses. 3.Use the techniques of theoretical chemistry for the same compounds to be studied experimentally, in an "interim" design strategy based on molecular determinants of activation at each in vivo endpoint. Implicit in this approach is the determination of common properties modulating recognition of all receptors involved in the particular endpoint considered. This strategy will lead to refinements of our current hypotheses that will be used to design activity-selective compounds that could be more targeted medications.

这一拟议的跨学科努力的总体目标继续是 计算机辅助设计新的治疗药物， 药理学特征，其通过结合到 BDZ/GABA-A受体（BDZR配体）。 为此，我们将继续（1） 验证当前关于非选择性配体的假设， BDZ/GABA-A受体识别的分子决定因素， 基于其抗惊厥终点的激活决定因素， 确定使用它们设计的有前途的药物。 这一目标将 （a）继续从理论上描述其他 文献中报告的化合物家族未包括 在用于假设发展的原始数据集中，以及B）综合， 两个家族的药理学评价 最初基于该假设提出的药理学特征：i） 氮杂吲哚; ii）吡咯并喹啉。2)提高对BDZ体外的认识 和体内药理学的发展， 生物学，以一种方式，也将导致一个适当的数据库， 假设细化和第二代类似物的设计。 到 为了实现这一目标，我们将：a）合成化合物的类似物， 据报道具有有趣的药理学特征， 可以用于i）探测受体异质性，因为它们的 选择性结合的能力，或ii）引起定性的不同 反应，即激动、拮抗、反向激动或无反应， 不同的行为终点，B）继续表征受体 异质性，解决中央BDZR的数量问题 使用不同大脑区域的亚型，据报道， 异质性和使用额外的配体; c）探索 氯离子通量作为激动剂、拮抗剂和逆转剂的指示 用于受体结合研究的每个脑区域中的激动剂活性; d）使用六个体内终点：抗焦虑药，抗惊厥药， 食欲过盛、镇静、肌肉松弛剂和体温过低，以表征 其他已知的家庭和新合成的，发现结合 对任何BDZ/GABA-A受体亚型具有显著亲和力。 目标 这些研究的目的是确定有希望的差异的能力， 一组选择的化合物来区别地引发这些活性。 这些结果将用于两个不同的目的：i）用作 用于设计活性特异性类似物的数据库，和ii）进一步 阐明识别给定亚型与 体内反应3.使用理论化学的技术， 在“过渡”设计中， 基于在每个体内激活的分子决定因素的策略 终点。 这种方法中隐含的是确定共同的 调节所有受体识别的特性， 考虑的特定端点。 这一战略将导致改进 我们目前的假设，将用于设计活动选择性 可以成为更有针对性的药物。