2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery
Aaron M. Bender, Lauren C. Parr, William B. Livingston, Craig W. Lindsley, W. David Merryman
Abstract
The cardiotoxicity associated with des -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT 2B ) 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 2B 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 2B in disease progression, as well as the development of drug-like and receptor subtype-selective 5-HT 2B 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 2B . Herein, it is our aim to examine the current state of 5-HT 2B drug discovery, with an emphasis on the receptor’s role in the central nervous system (CNS) versus the periphery.