Yasgar Adam, Simeonov Anton
National Institutes of Health, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences , Bethesda, MD , USA +1 301 217 5721 ; +1 301 217 5736 ;
Expert Opin Drug Discov. 2014 Nov;9(11):1319-31. doi: 10.1517/17460441.2014.956721. Epub 2014 Sep 24.
Much has been presented and debated on the topic of drug abuse and its multidimensional nature, including the role of society and its customs and laws, economical factors, and the magnitude and nature of the burden. Given the complex nature of the receptors and pathways implicated in regulation of the cognitive and behavioral processes associated with addiction, a large number of molecular targets have been interrogated during recent years to discover starting points for development of small-molecule interventions.
This review describes recent developments in the field of early drug discovery for drug abuse interventions with an emphasis on the advances published during the 2012 - 2014 period.
Technologically, the processes/platforms utilized in drug abuse drug discovery are nearly identical to those used in the other disease areas. A key complicating factor in drug abuse research is the enormous biological complexity surrounding the brain processes involved and the associated difficulty in finding 'good' targets and achieving exquisite selectivity of treatment agents. While tremendous progress has been made during recent years to use the power of high-throughput technologies to discover proof-of-principle molecules for many new targets, next-generation models will be especially important in this field. Examples include: seeking advantageous drug-drug combinations, the use of automated whole-animal behavioral screening systems, advancing our understanding of the role of epigenetics in drug addiction and the employment of organoid-level 3D test platforms (also referred to as tissue-chip or organs-on-chip).
关于药物滥用及其多维度性质的话题,已有诸多论述和探讨,包括社会及其习俗与法律的作用、经济因素以及负担的程度和性质。鉴于参与调节与成瘾相关的认知和行为过程的受体及途径具有复杂的性质,近年来人们研究了大量分子靶点,以寻找小分子干预措施的开发起点。
本综述描述了药物滥用干预早期药物发现领域的最新进展,重点关注2012年至2014年期间发表的进展。
从技术上讲,药物滥用药物发现中使用的过程/平台与其他疾病领域所使用的几乎相同。药物滥用研究中的一个关键复杂因素是围绕所涉及的大脑过程存在巨大的生物学复杂性,以及在寻找“良好”靶点和实现治疗药物的精准选择性方面存在相关困难。虽然近年来利用高通量技术的力量为许多新靶点发现原理验证分子方面取得了巨大进展,但下一代模型在该领域将尤为重要。例如:寻找有利的药物组合、使用自动化全动物行为筛选系统、加深我们对表观遗传学在药物成瘾中的作用的理解以及采用类器官水平的3D测试平台(也称为组织芯片或芯片上器官)。