Department of Immunology, Merck Research Laboratories , BMB 10-108, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
J Med Chem. 2014 Aug 28;57(16):6887-96. doi: 10.1021/jm401677g. Epub 2014 Apr 29.
Seven transmembrane receptors (7TMRs), also known as G-protein-coupled receptors (GPCRs), have proven to be valuable targets for the development of therapeutics. The expansion of our understanding of 7TMR downstream signaling pathways beyond G-proteins has broadened our appreciation of the versatility of these cell surface receptors. In particular, the increased awareness of 7TMR engagement of β-arrestin signaling has opened up additional avenues for drug discovery. 7TMRs can adopt different conformations and in response to various ligands can lead to a bias in downstream signaling mechanisms when comparing the overall efficacy between G-protein and β-arrestin dependent pathways. In 2012, we organized a session at the Spring National Meeting of the American Chemical Society on biased signaling in 7TMRs.1-4 Building on that experience, we provide in this Miniperspective some examples that exemplify developments in the area of biased 7TMR signaling and highlight some cautionary notes as well as some of the exciting opportunities for drug discovery.
七次跨膜受体（7TMRs），也称为 G 蛋白偶联受体（GPCRs），已被证明是开发治疗药物的有价值的靶点。我们对 7TMR 下游信号通路的理解超出了 G 蛋白的范围，这拓宽了我们对这些细胞表面受体多功能性的认识。特别是，人们越来越意识到 7TMR 与β-arrestin 信号的结合为药物发现开辟了更多途径。7TMR 可以采用不同的构象，并且在响应各种配体时，与 G 蛋白和β-arrestin 依赖性途径之间的整体功效相比，可能导致下游信号机制出现偏向。2012 年，我们在美国化学学会春季全国会议上组织了一次关于 7TMR 中偏向信号的会议。1-4 在此基础上，我们在这篇小综述中提供了一些示例，这些示例体现了偏向性 7TMR 信号方面的发展，并强调了一些注意事项以及药物发现的一些令人兴奋的机会。
