Suckow Arthur T, Briscoe Celia P
MedImmune, LLC, Gaithersburg, MD, 20878, USA.
Epigen Biosciences, 10225 Barnes Canyon Rd, San Diego, CA, 92121, USA.
Handb Exp Pharmacol. 2017;236:101-131. doi: 10.1007/164_2016_45.
The identification of fatty acids as ligands for the G-protein coupled free fatty acid (FFA) receptor family over 10 years ago led to intensive chemistry efforts to find small-molecule ligands for this class of receptors. Identification of potent, selective modulators of the FFA receptors and their utility in medicine has proven challenging, in part due to their complex pharmacology. Nevertheless, ligands have been identified that are sufficient for exploring the therapeutic potential of this class of receptors in rodents and, in the case of FFA1, FFA2, FFA4, and GPR84, also in humans. Expression profiling, the phenotyping of FFA receptor knockout mice, and the results of studies exploring the effects of these ligands in rodents have uncovered a number of indications where engagement of one or a combination of FFA receptors might provide some clinical benefit in areas including diabetes, inflammatory bowel syndrome, Alzheimer's, pain, and cancer. In this chapter, we will review the clinical potential of modulating FFA receptors based on preclinical and in some cases clinical studies with synthetic ligands. In particular, key aspects and challenges associated with small-molecule ligand identification and FFA receptor pharmacology will be addressed with a view of the hurdles that need to be overcome to fully understand the potential of the receptors as therapeutic targets.
10多年前，脂肪酸被鉴定为G蛋白偶联游离脂肪酸（FFA）受体家族的配体，这引发了人们在化学领域的大量研究，以寻找这类受体的小分子配体。事实证明，鉴定FFA受体的强效、选择性调节剂及其在医学上的应用具有挑战性，部分原因在于其复杂的药理学特性。尽管如此，已经鉴定出了一些配体，它们足以在啮齿动物中探索这类受体的治疗潜力，对于FFA1、FFA2、FFA4和GPR84受体，在人类中也具有探索价值。表达谱分析、FFA受体基因敲除小鼠的表型分析，以及在啮齿动物中探索这些配体作用效果的研究结果，揭示了一些疾病指征，在这些疾病中，激活一种或多种FFA受体可能在糖尿病、炎症性肠综合征、阿尔茨海默病、疼痛和癌症等领域带来一定的临床益处。在本章中，我们将基于临床前研究以及部分情况下的临床研究，回顾使用合成配体调节FFA受体的临床潜力。特别是，我们将探讨与小分子配体鉴定和FFA受体药理学相关的关键方面和挑战，着眼于充分理解这些受体作为治疗靶点的潜力时需要克服的障碍。
