Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the inflammatory response. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target for several diseases, such as obesity, metabolic syndrome, non-alcoholic steatohepatitis, cholestasis and chronic inflammatory diseases of the liver and intestine. However, most of the currently available compounds impact on all discovered FXR-mediated functions and may have, on top of beneficial effects, undesired biological actions depending on the disease. Therefore, research efforts are increasingly focused on the development of selective FXR modulators, i.e. selective bile acid receptor modulators (SBARMs), aimed at limiting the potential side-effects of conventional full FXR agonists upon chronic treatment.

Here, we review the rationale for the design of SBARMs comprising dissociation between metabolic and inflammatory signaling, gene-selective and tissue-specific targeting. We discuss the potential structural mechanisms underlying the binding properties of dissociating ligands of FXR in light of ongoing efforts on the generation of dissociated ligands for otxher nuclear receptors, as well as their pharmacological and therapeutic potential.

胆汁酸是两亲性分子，以前在餐后条件下可在肠道中充当脂肪增溶剂。在过去的二十年中，胆汁酸已被认为是通过法尼醇X受体（FXR）等调控能量代谢途径的信号分子。胆汁酸活化后，FXR控制胆汁酸，脂质，葡萄糖和氨基酸代谢中涉及的基因的表达。另外，已经表明FXR激活限制了炎症反应。FXR在代谢和炎症各个方面的核心作用使FXR成为多种疾病的引人注目的药物靶标，例如肥胖，代谢综合征，非酒精性脂肪性肝炎，胆汁淤积以及肝和肠的慢性炎症性疾病。然而，大多数当前可用的化合物都会影响所有已发现的FXR介导的功能，并且除了有益作用之外，还可能具有取决于疾病的不良生物作用。因此，研究努力越来越集中在选择性FXR调节剂，即选择性胆汁酸受体调节剂（SBARM）的开发上，旨在限制常规全FXR激动剂对慢性治疗的潜在副作用。

在这里，我们回顾了SBARMs设计的基本原理，包括代谢和炎症信号，基因选择性和组织特异性靶向之间的分离。根据正在进行的针对其他核受体的解离配体的产生以及它们的药理和治疗潜力，我们讨论了FXR解离配体的结合特性背后的潜在结构机制。