Parallel functional activity profiling reveals valvulopathogens are potent 5-HT2B receptor agonists: implications for drug safety assessment. Molecular pharmacology [Mol Pharmacol] Journal article

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-HT2B receptor agonists. We have shown that activation of 5-HT2B 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 about 2,200 FDA-approved or investigational medications to identify 5-HT2B receptor agonists, using calcium-based HTS. Of these 2,200 compounds, 58 were 5-HT2B receptor agonists (hits); most of these had previously been identified as 5-HT2B receptor agonists, including seven bona fide valvulopathogens. Six of the newly identified hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled," i.e., assayed in parallel for 5-HT2B receptor agonism using multiple readouts in order 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 pEC50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. In toto, our data demonstrate that patterns of 5-HT2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

Molecular pharmacology [Mol Pharmacol]