MOLECULAR MODELING, DESIGN, & EVALUATION OF BDZ LIGANDS

描述：(申请人摘要) 这项拟议的跨学科努力的总体目标仍然是 苯二氮卓类受体(BDZR)的药理表征及设计 通过这些受体发挥作用的行为选择性配体。的设计 这些新的治疗药物将专注于两个策略：设计 与小脑“I型”BDZR结合的配体及其活性设计 特定的类比。1)BDZR的当前三维药效团 将用于a)修饰通过搜索发现的先导化合物 3D数据库和b)通过以下方式设计候选“I型”选择性拮抗剂 使用我们的激活标准对选择性激动剂进行修饰。这个 进一步了解BDZR药理学的目标将在 三种方法：a)确定一种新的阿尔卑斯不敏感的BDZR亚型 通过确定它是否存在于大鼠脊髓膜中来鉴定 其他大脑区域和开发3D药效团识别 B)继续探索受体的异质性，通过解决 关于几个额外脑中中枢BDZR亚型数目的问题 利用傅里叶派生的亲和光谱分析区域 成功地表征了脊髓中受体的异质性 当前授权期，并在已知的接收系统中进行验证；c) 确定在这些不同大脑中识别的所有位置的亲和力 在我们目前的研究中发现的配体的区域 表现出行为的异质性。2)活动特定类比的设计 将在多步骤战略中实现，其基础是确定 候选受体识别和激活的分子决定因素 参与每个体内终点的调解。这些步骤是：a) 介导体内特定终点的受体的鉴定 那些在该终点没有活性的化合物不与之结合的化合物 显著的亲和力；b)开发3D识别药效团 通过识别每个候选受体共同的计算属性 高亲和力但在低亲和力化合物中不存在；c)形成一种 调节特定终点的每个受体的激活药效团 通过鉴定激动剂、拮抗剂和 反向激动剂；d)使用3D药效团进行识别和 与要搜索3D数据库的每个行为端点相关的激活 符合这些标准的新化合物；e)获得或合成 筛选出的化合物及其与BDZRs结合能力的评价 不同的大脑区域；高亲和力类似物在每个 确定其活动程度的五个行为端点 配置文件与预测的行为相匹配，并识别选择性活动 类比。

DESCRIPTION: (Applicant's Abstract) The overall goals of this proposed interdisciplinary effort continue to be characterization of benzodiazepine receptor (BDZR) pharmacology and design of behavioral selective ligands that act through these receptors. Design of these novel therapeutic agents will focus on two strategies: design of ligands that bind to the cerebellar "Type I" BDZR and design of activity specific analogs. 1) the current 3D pharmacophore for the "Type I" BDZR will be used to a) modify lead compounds that were discovered by searching 3D databases and b) design candidate "Type I" selective antagonists by modification of selective agonists using our criteria for activation. The goal of further understanding of BDZR pharmacology will be addressed in three ways: a) determining if a novel alpidem-insensitive BDZR subtype identified in rat spinal cord membranes by determining if it is present in other brain regions and developing a 3D pharmacophore for recognition of this site; b) continuing to probe receptor heterogeneity by addressing the question of the number central BDZR subtypes in several additional brain regions using Fourier-derived affinity spectrum analysis used to successfully characterize receptor heterogeneity in spinal cord during the current grant period and validated in a known receptor system; c) determining the affinities at all sites identified in these different brain regions of the ligands that have been found in our current studies to display behavioral heterogeneity. 2) Design of activity specific analogs will be achieved in a multistep strategy based on identification of molecular determinants of recognition and activation at candidate receptors involved in mediation of each in vivo endpoint. These steps are: a) identification of receptors that mediate a particular in vivo endpoint as those to which compounds that are inactive at that endpoint do not bind with significant affinity; b) development of a 3D recognition pharmacophore for each candidate receptor by identification of calculated properties common to high affinity but absent in low affinity compounds; c) development of an activation pharmacophore for each receptor mediating a particular endpoint by identifying properties that are different among agonists, antagonists and inverse agonists; d) use of the 3D pharmacophores for recognition and activation relevant to each behavioral endpoint to search 3D databases for novel compounds that satisfy these criteria; e) acquisition or synthesis of selected compounds and evaluation for their ability to bind to BDZRs in different brain regions; evaluation of high affinity analogs at each of the five behavioral endpoints to determine to what extent their activity profiles match the predicted behavior and to identify activity selective analogs.