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

Abstract

Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas.

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…462,463 The biased agonism of ergotamine and LSD was demonstrated to be β-arrestin-biased signaling. 2,464 In addition, LY266097 (a selective 5-HT 2B antagonist, 186, Figure 26) was also found to have biased signaling that correlates with transmembrane domain 7 in EBP. 463 In 2016, a new array of (2,3-dihydro)benzofuran-based compounds was prepared and evaluated as selective 5-HT 2C biased agonist.…”

“…Furthermore, several 5-HT 2A receptor antagonists, such as ritanserin and setoperone, also display a functionally selective manner, which is likely caused by redistribution of the receptors from the cell surface to intracellular compartments . For 5-HT 2B receptors, the binding of ergotamine and LSD revealed two binding sites: a presumed orthosteric binding pocket, which is shared with serotonin, and an extended binding pocket (EBP), which encompasses extracellular portions and has been proposed to likely facilitate biased signaling. , The biased agonism of ergotamine and LSD was demonstrated to be β-arrestin-biased signaling. , In addition, LY266097 (a selective 5-HT 2B antagonist, 186 , Figure ) was also found to have biased signaling that correlates with transmembrane domain 7 in EBP . In 2016, a new array of (2,3-dihydro)­benzofuran-based compounds was prepared and evaluated as selective 5-HT 2C biased agonist .…”

Development of Pharmacophore Models for the Important Off-Target 5-HT2B Receptor

“…All ligands of the published cocrystal structures share a salt bridge between their positively charged nitrogen and the carboxylate of D135. Furthermore, all ergoline-containing compounds form π–π-stacking interactions with F341 in helix VI . Besides, several hydrophobic interactions between hydrophobic fragments or aromatic rings of the ligands can be observed with residues in the OBP in helices III, V, VI, and VII and residues in the EBP in helices III, VII, and the second extracellular loop.…”

“…Furthermore, all ergoline-containing compounds form π−π-stacking interactions with F341 in helix VI. 26 Besides, several hydrophobic interactions between hydrophobic fragments or aromatic rings of the ligands can be observed with residues in the OBP in helices III, V, VI, and VII and residues in the EBP in helices III, VII, and the second extracellular loop. Based on this information, Wang et al 26 describe a first static 5-HT 2Bpharmacophore model which consists of a positive electrostatic, hydrogen bond donor, and hydrophobic features while noting that none of the cocrystal ligands fit well in this pharmacophore model.…”

“…In the cardiovascular system, 5-HT 2B is expressed in myocardial, endothelial, and vascular smooth muscle cells, and agonism is involved in cardiovascular diseases including cardiomyopathy, valvular heart disease (VHD), − and pulmonary arterial hypertension. ,− Drug-induced VHD was the cause of the withdrawal of fenfluramine and dexfenfluramine used for the indication of obesity from the U.S. market in 1997 and pergolide used for the indication of Parkinson’s disease in 2007. These compounds are partial or full agonists of 5-HT 2B with high affinity, and the pathogenesis of drug-induced VHD could be correlated with off-target activation of 5-HT 2B . ,, Furthermore, 5-HT 2B could be linked to the vascular heart diseases such as mitral valve prolapse and its involvement in calcific aortic valve disease; , fibrosis disorders such as liver fibrosis, − pulmonary fibrosis, − systemic sclerosis, − and pancreatic fibrosis; different types of cancer including hepatocellular carcinoma, − neuroendocrine tumor, , and pancreatic ductal adenocarcinomas; and irritable bowel syndrome of the gastrointestinal tract. − …”