Hudson B D, Smith Nicola J, Milligan Graeme
Molecular Pharmacology Group, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
Adv Pharmacol. 2011;62:175-218. doi: 10.1016/B978-0-12-385952-5.00006-3.
The G protein-coupled receptors (GPCRs) are extremely successful drug targets, with recent estimates suggesting that approximately 30% of all currently available therapeutics act at these receptors. Despite this success, only a small number of the over 400 known nonodorant GPCRs are currently targeted, suggesting there is still untapped therapeutic potential. However, as most GPCRs were identified based on their sequence homology to other members of the superfamily, many still remain "orphan" receptors without known ligands. Indeed, even once a GPCR has been deorphanized, the receptor typically is still poorly characterized in terms of its pharmacology and biological functions, presenting a unique set of experimental challenges in order to define its therapeutic potential. We discuss some of these challenges and how they have been addressed in order to uncover the therapeutic potential of five recently deorphanized receptors that are activated by short- and long-chain free fatty acids.
G蛋白偶联受体（GPCRs）是极为成功的药物靶点，最近的估计表明，目前所有可用治疗药物中约有30%作用于这些受体。尽管取得了这样的成功，但在400多种已知的非嗅觉GPCRs中，目前只有少数被作为靶点，这表明仍有未开发的治疗潜力。然而，由于大多数GPCRs是基于它们与超家族其他成员的序列同源性而被鉴定出来的，许多仍然是没有已知配体的“孤儿”受体。事实上，即使一个GPCRs的“孤儿”身份被解除，该受体在药理学和生物学功能方面通常仍缺乏充分的特征描述，为了确定其治疗潜力，这带来了一系列独特的实验挑战。我们将讨论其中的一些挑战，以及为了揭示由短链和长链游离脂肪酸激活的五个最近解除“孤儿”身份的受体的治疗潜力，这些挑战是如何被应对的。
