MOLECULAR MODELING, DESIGN AND EVALUATION OF BDZ LIGANDS

这项拟议的跨学科努力的总体目标继续 是计算机辅助设计的新的治疗药物与改进 药理特征，通过结合 BDZ/GABA-A受体(BDZR配体)。为此，我们将继续1) 验证非选择性配体的现有假设，包括共同 BDZ/GABA-A受体识别的分子决定因素(S)和 基于其抗惊厥终点的激活决定因素和 确定使用它们设计的有前景的药物。这个目标将是 完成者：a)继续从理论上描述其他 文献中报道的未被纳入的化合物家族 在用于假设开发的原始数据集中，以及b)综合和 预测的两个家系的药理学评价 最初基于这一假设提出的药理图谱：i) 氮杂环己烷；ii)吡咯喹啉。2)提高对BDZ的体外认识 和体内药理学根据分子生物学的新发展 生物学，以一种方式也将导致一个适当的数据库 第二代类比的假设改进和设计。至 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特征， 可能有助于i)探测受体的异质性，因为它们 有选择性地结合的能力或ii)引起质的不同 反应，即激动型、拮抗型、反向激动型或无反应 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报告具有有限的亚型 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标 用于受体结合研究的每个脑区的激动剂活性； D)使用体内的六个终点：抗焦虑、抗惊厥、 吞噬功能亢进、镇静、肌肉松弛和体温过低 其他已知的家族和新合成的家族，发现与 与任何BDZ/GABA-A受体亚型具有显著的亲和力。目标是 这些研究中的一项就是确定有希望的差异 一组选择的化合物，以不同的方式诱导这些活性。 这些结果将用于两个不同的目的：i)作为 用于设计特定活动类比的数据库和二)进一步 阐明对给定亚型的识别与In之间的关系 活体反应。3.运用理论化学技术进行 同样的化合物将在“临时”设计中进行实验研究 基于活体内激活的分子决定因素的策略 终结点。在这种方法中隐含的是共同的决定 调节识别参与的所有受体的特性 考虑了特定的端点。这一战略将导致改进 我们目前的假设将被用来设计活动选择性 可能是更有针对性的药物的化合物。

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.