Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists

Abstract

The current review summarizes the limited progress made in the past decade for design and development of 5-HT2BR antagonists for the treatment of disorders related to heart. We focus primarily on the different scaffolds reported in both manuscripts and patents, that have led to selectivity for 5-HT2B over subtype 5-HT2A/2C. Opportunities in cardiovascular drug development for novel 5-HT2BR antagonists are also presented.

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…Fully formed heart valves consist of valvular endothelial cells and valvular interstitial cells (VICs). The two types of cells regulate the generation of the extracellular matrix (ECM) and thus play critical roles in valve function [2]. Excessive ECM alters valve structure and leads to VHD.…”

“…Drug-induced VHD has led to the withdrawal of fenfluramine and dexfenfluramine from the U.S. market in 1997, followed by the withdrawal of pergolide in 2007. Either these drugs or their metabolites have been demonstrated to be partial or full 5-HT 2B R agonists with high affinity, and the pathogenesis of drug-induced VHD was correlated to the "off-target" activation of the 5-HT 2B R [2,18]. Consequently, drug candidates with possible 5-HT 2B R agonism effects are now required to be evaluated before approval [19].…”

“…Consequently, drug candidates with possible 5-HT 2B R agonism effects are now required to be evaluated before approval [19]. Additionally, the signaling mechanism of drug-induced VHD has been studied [2,20]. Apart from the canonical G q/11 signal transduction pathway involved in the activation of PLCβ and PKC, the activation of the 5-HT 2B R may also activate mitogenic pathways through the phosphorylation of the Src kinase and extracellular regulated kinases (ERK) and further enhance the activity of the transforming growth factor β (TGF-β).…”

“…5-Hydroxytryptamine (5-HT), or serotonin, was first isolated from beef serum and characterized in the late 1940s [1]. Biochemically, 5-HT is derived from the amino acid tryptophan, undergoing hydroxylation and decarboxylation processes that are catalyzed by tryptophan hydroxylase and aromatic L-amino acid decarboxylase, respectively [2]. As a biogenic amine, 5-HT plays important roles in cardiovascular function, bowel motility, platelet aggregation, hormone release, and psychiatric disorders [2].…”

“…Biochemically, 5-HT is derived from the amino acid tryptophan, undergoing hydroxylation and decarboxylation processes that are catalyzed by tryptophan hydroxylase and aromatic L-amino acid decarboxylase, respectively [2]. As a biogenic amine, 5-HT plays important roles in cardiovascular function, bowel motility, platelet aggregation, hormone release, and psychiatric disorders [2]. 5-HT achieves its physiological functions by targeting various 5-HT receptors (5-HTRs), which are composed of six classes of G protein-coupled receptors (GPCRs) (5-HT 1 , 5-HT 2 , 5-HT 4 , 5-HT 5 , 5-HT 6, and 5-HT 7 receptors, a total of 13 subtypes) and a class of cation-selective ligand-gated ion channels, the 5-HT 3 receptor [3].…”