Pharmacosynthetics: Reimagining the pharmacogenetic approach.-猫眼课题宝

DOI：

10.1016/j.brainres.2012.09.043

发表时间：

2013-05-20

期刊：

Brain research

影响因子：

2.9

通讯作者：

中科院分区：

医学3区

文献类型：

作者：

Farrell MS;Roth BL

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562395/?report=classic

药理学，在其最广泛的解释，被定义为生理实体和药物之间的相互作用的研究。在现代神经精神药理学中，这种相互作用被视为一方面是药物本身，另一方面是信号转导（受体），信号转导级联（效应蛋白，第二信使），细胞反应（转录调节，活性调节），器官反应（脑电路调节），最后是整个生物体的反应（行为）。换句话说，药理学围绕着这样一个想法构建自己：外源性分子（药物）编码一个“信号”，导致另一边的一切，包括在极端情况下的生理反应。推论是，在确定的细胞类型中参与特定的信号转导途径必然导致原型生理反应。因此，例如，大鼠主动脉平滑肌细胞中5-HT 2A受体的多巴胺能激活导致细胞内Ca++增加（通过IP 3释放）和平滑肌收缩。在这里，我们建议，合成配体- GPCR对（又名DREADDs，RASSLS，“药物遗传学”）的发明允许使用移动方程的药理学研究：更多的信号转导元件移动到左边，随后，在实验控制下。为了消除歧义，并澄清这一新的解释作为一个创造的药理学操作，我们提出的术语药物合成来描述迄今为止被称为药物遗传学或化学遗传学。这篇评论讨论了这种新的解释，并回顾了最近的应用程序的技术和考虑的方法。

Pharmacology, in its broadest interpretation, is defined as the study of the interaction between physiological entities and drugs. In modern neuropsychopharmacology, this interaction is viewed as the drug itself on one side and signal transducer (receptor), the signal transduction cascade (effector proteins, second messengers), the cellular response (transcriptional regulation, activity modulation), the organ response (brain circuitry modulation), and, finally, the whole organism response (behavior) on the other. In other words, pharmacology has structured itself around the idea that the exogenous molecule (the drug) encodes a “signal” leading to everything on the other side including, in extreme renditions, a physiological response. The inference is that engaging a particular signal transduction pathway in a defined cell type leads inexorably to a prototypic physiological response. Thus, for instance, serotonergic activation of 5-HT2A receptors in rat aortic smooth muscle cells leads to an increase in intracellular Ca++ (via IP3 release) and smooth muscle contraction. Here, we suggest that the invention of synthetic ligand – GPCR pairs (aka DREADDs, RASSLS, ‘pharmacogenetics’) permits the study of pharmacology using a shifted equation: more of the signal transduction elements moved to the left and, subsequently, under experimental control. For the purposes of disambiguation and to clarify this new interpretation as a creation of pharmacological manipulation, we present the term pharmacosynthetics to describe what has heretofore been called pharmacogenetics or chemicogenetics. This review discusses this new interpretation and reviews recent applications of the technology and considerations of the approach.