Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
J Med Chem. 2023 Aug 24;66(16):11027-11039. doi: 10.1021/acs.jmedchem.3c01178. Epub 2023 Aug 16.
The cardiotoxicity associated with -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT) has solidified the receptor's place as an "antitarget" in drug discovery. Conversely, a growing body of evidence has highlighted the utility of 5-HT antagonists for the treatment of pulmonary arterial hypertension (PAH), valvular heart disease (VHD), and related cardiopathies. In this Perspective, we summarize the link between the clinical failure of fenfluramine-phentermine (fen-phen) and the subsequent research on the role of 5-HT in disease progression, as well as the development of drug-like and receptor subtype-selective 5-HT antagonists. Such agents represent a promising class for the treatment of PAH and VHD, but their utility has been historically understudied due to the clinical disasters associated with 5-HT. Herein, it is our aim to examine the current state of 5-HT drug discovery, with an emphasis on the receptor's role in the central nervous system (CNS) versus the periphery.
与 -乙基-右旋芬氟拉明（norDF）和相关的血清素受体 2B（5-HT）激动剂相关的心脏毒性已经确定了该受体作为药物发现中的“抗靶标”的地位。相反，越来越多的证据强调了 5-HT 拮抗剂在肺动脉高压（PAH）、瓣膜性心脏病（VHD）和相关心脏疾病治疗中的应用。在本观点中，我们总结了芬氟拉明-苯丁胺（fen-phen）的临床失败与随后对 5-HT 在疾病进展中的作用的研究之间的联系，以及类似药物和受体亚型选择性 5-HT 拮抗剂的发展。这些药物代表了治疗 PAH 和 VHD 的一类有前途的药物，但由于与 5-HT 相关的临床灾难，它们的应用在历史上一直受到低估。在此，我们旨在检查 5-HT 药物发现的现状，重点关注受体在中枢神经系统（CNS）与外周组织中的作用。
