2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery

The cardiotoxicity associated with des-ethyl-dexfen-fluramine(norDF) and related agonists of the serotonin receptor 2B (5-HT2B) has solidified the receptor's place as an "antitarget"in drug discovery. Conversely, a growing body of evidence has highlightedthe utility of 5-HT2B antagonists for the treatment ofpulmonary arterial hypertension (PAH), valvular heart disease (VHD),and related cardiopathies. In this Perspective, we summarize the linkbetween the clinical failure of fenfluramine-phentermine (fen-phen)and the subsequent research on the role of 5-HT2B in diseaseprogression, as well as the development of drug-like and receptorsubtype-selective 5-HT2B antagonists. Such agents representa promising class for the treatment of PAH and VHD, but their utilityhas been historically understudied due to the clinical disasters associatedwith 5-HT2B. Herein, it is our aim to examine the currentstate of 5-HT2B drug discovery, with an emphasis on thereceptor's role in the central nervous system (CNS) versusthe periphery.