Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, United States.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, United States.
Biochem Pharmacol. 2014 Jan 1;87(1):25-39. doi: 10.1016/j.bcp.2013.07.027. Epub 2013 Aug 8.
The application of detailed quantitative analyses of the concentration dependence of the biological responses mediated by endogenous hormones and other mediators, drugs, and related compounds has been the foundation of pharmacology for the past century or more. This approach has been remarkably successful in identifying the specific molecular targets for these mediators and drugs, in establishing the mechanisms for those effects at both the cellular and whole organismal levels, and in the development of new chemical entities (NCEs) with great selectivity for individual molecular targets. The availability of such compounds has unfortunately led to a mindset that detailed quantitative analyses are no longer necessary to use such compounds in understanding biological system function and to draw valid conclusions in regard to the utility of NCEs selective for putative drug targets in the potential treatment of human disease states. This lack of appreciation for quantitative approaches has contributed significantly to the all-too-frequent failures of new drug candidates in early-stage clinical trials. The present article reviews basic drug/receptor concepts together with the mathematical relationships that underlie the quantitative analysis of dose-response and concentration-effect relationships for individual compounds and for more complex systems, such as the comparative analysis of multiple compounds at a single receptor. A thorough understanding of these concepts and their associated analyses, along with their proper and rigorous application in all pre-clinical drug development studies, is an essential component of an integrated approach toward improving drug development.
详细的定量分析应用于内源性激素和其他介质、药物及相关化合物介导的生物反应的浓度依赖性，一直是过去一个多世纪药理学的基础。这种方法在确定这些介质和药物的特定分子靶点方面非常成功，在确定细胞和整体水平的这些效应的机制方面也非常成功，并且在开发对个体分子靶点具有高选择性的新化学实体 (NCE) 方面也非常成功。不幸的是，这些化合物的出现导致了一种思维模式，即认为在理解生物系统功能和得出关于针对假定药物靶点的 NCE 的有效性的结论时，不再需要详细的定量分析来使用这些化合物。这种对定量方法的缺乏认识，极大地促成了新药候选物在早期临床试验中频繁失败。本文综述了基本的药物/受体概念，以及为单个化合物和更复杂系统（如单个受体的多种化合物的比较分析）的剂量反应和浓度效应关系的定量分析提供基础的数学关系。透彻理解这些概念及其相关分析，并在所有临床前药物开发研究中正确、严格地应用这些概念及其相关分析，是改善药物开发的综合方法的重要组成部分。
