Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine_2BReceptor Agonists: Implications for Drug Safety Assessment

Abstract

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine 2B (5-HT 2B ) receptor agonists. We have shown that activation of 5-HT 2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT 2B receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT 2B receptor agonists (hits); 14 of these had previously been identified as 5-HT 2B receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twentythree of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT 2B receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC 50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT 2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.In 1997, the anorexigen fenfluramine was voluntarily withdrawn from the U.S. market because of its association with valvular heart disease (VHD) and pulmonary hypertension

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

“…STI-571 is a protein-tyrosine kinase inhibitor, which selectively blocks Abl, c-kit, and PDGFR, 34 but has no 5-HT 2B R agonist or antagonist properties (see supplemental data of Huang et al 35 ). Expression of PDGFR was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients and beneficial action of STI-571 has been proposed to act directly at lung PDGFR, 36 which is well known to mediate SMC proliferation.…”

Kinetics of 5-HT2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

“…Activation of the receptor on heart valve interstitial cells is believed to result in abnormal deposition of extracellular matrix components, resulting in thickening of valve leaflets, ultimately producing valvular insufficiency or valvulopathy (Fitzgerald et al, 2000;Rothman et al, 2000;Huang et al, 2009;Rothman and Baumann, 2009;Elangbam, 2010;Hutcheson et al, 2011). The appetite suppressant fenfluramine, perhaps the most notorious valvulopathogen, was withdrawn from the US market in 1997.…”

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

“…Essentially, inverse agonists are antagonists with negative intrinsic activity. Finally, drugs like ergotamine display functional selectivity or signaling bias for many 5-HT receptors including 5-HT 2B (28,29). Thus, ergotamine has much higher potency for activating β-arrestin pathways than for activating G protein-mediated signaling (28,29) and as such is considered to display functional selectivity for β-arrestin signaling and to represent a β-arrestin-biased agonist.…”

“…5-HT 2A receptors represent the main serotonin receptors found in platelets, vascular smooth muscle, and the cerebral cortex (25,26). As discussed below, 5-HT 2B receptors are enriched in the heart (27), and drugs likely mediate their valvulopathogenic actions on heart valves via a combination of G protein and β-arrestin signaling (27)(28)(29). The distribution and function of 5-HT 2C receptors will be summarized below when lorcaserin, a selective 5-HT 2C agonist, is discussed.…”