Pharmacology of Connexin Channels: Structure-Activity Studies.

描述（由申请人提供）：称为连接蛋白的多基因蛋白质家族形成细胞间间隙连接，直接介导相邻细胞之间的信号传导。这些细胞-细胞通道由来自相邻细胞的两个半通道或所谓的连接子组成。除了形成间隙连接之外，连接蛋白家族的一些成员还可以在未对接状态下充当跨膜离子通道。因此，连接蛋白可以参与介导跨质膜以及细胞之间的信号传导。连接蛋白形成的细胞-细胞通道和半通道在许多不同的细胞类型和组织中发挥着各种各样的作用，如使用遗传和分子方法的许多研究所强调的。连接蛋白通道也被认为是治疗癫痫、心律失常、癌症、中风、特发性震颤和降低缺血后细胞死亡程度的新的和有前景的药理学靶点。然而，在识别和表征这些通道的特异性和高亲和力抑制剂，这将大大有助于调查其生理和病理生理作用的进展，不幸的是一直缓慢。为了确定抑制连接蛋白通道的新型药物，我们于2006年7月与加州大学戴维斯分校的Heike Wulff博士合作，该实验室专门设计小分子离子通道调节剂。通过筛选少量化合物从Wulff博士的图书馆丰富的离子通道调节剂，我们已经确定了四个新的小分子化学型，抑制连接蛋白通道在这个补助金的建议，我们建议广泛探测这些分子的SAR使用经典的药物化学方法，最终目标是开发一个高亲和力，特异性抑制剂（S）连接蛋白通道。公共卫生相关性：被称为连接蛋白的蛋白质在人类生理和疾病中发挥着广泛的作用。然而，没有药理学工具来评估它们在人类生物学中的作用或确定它们在预防/治愈某些类型疾病中的治疗效用。拟议的研究旨在开发这类通道的药理学试剂。

DESCRIPTION (provided by applicant): The multi-gene family of proteins called connexins form intercellular gap junctions that directly mediate signaling between adjacent cells. These cell-cell channels consist of two hemichannels or so-called connexons from adjacent cells. In addition to forming gap junctions, some members of the connexin family can also function as transmembrane ion channels in the undocked state. Thus, connexins can participate in mediating signaling across the plasma membrane as well as between cells. Both cell-cell channels and hemichannels formed by connexins play a wide variety of roles in a number of different cell types and tissues, as highlighted by numerous studies using genetic and molecular approaches. Connexin channels have also been proposed as new and promising pharmacological targets in the treatment of epilepsy, cardiac arrhythmia, cancer, stroke, essential tremor, and in reducing the extent of cell death following ischemia. However, progress in the identification and characterization of specific and high-affinity inhibitors of these channels, which would greatly assist in the investigation of their physiological and pathophysiological roles, has been unfortunately slow. With the goal of identifying new classes of drugs that inhibit connexin channels, we initiated a collaboration with Dr. Heike Wulff at UC Davis in July 2006, whose laboratory specializes in the design of small molecule ion channel modulators. Through screening of a small number of compounds from Dr. Wulff's libraries enriched in ion channel modulators we have already identified four new small molecule chemotypes that inhibit connexin channels In this grant proposal, we propose to extensively probe the SAR of these molecules using a classical medicinal chemistry approach with the ultimate goal of developing a high-affinity, specific inhibitor(s) of connexin channels. PUBLIC HEALTH RELEVANCE: Proteins called connexins play a wide variety of roles in human physiology and disease. However there are no pharmacological tools to evaluate their role in human biology or to determine their therapeutic utility in prevention/cure of certain types of diseases. Proposed studies are aimed at the development of pharmacological agents for this class of channels.