The Discovery of 5-HT2B Receptor Pharmacology Through the Understanding of Drug-Induced Valvulopathy

Chronic valvular heart disease (VHD) with myxomatous degeneration and thickening of the mitral valve leaflets is a deleterious side effect of many drugs targeting the serotonergic system. It is due to the poor selectivity of these old drugs and thus stimulation of 5-HT2 receptors as off targets by either the main compound or their metabolites. Consequently, many drugs are now withdrawn from the market due to VHD development, and because binding of 5-HT2B receptor refers to as a “black box warning”. However, 5-HT2 receptors are involved in many pathological conditions and represent promising targets for the development of new drugs. Thus, a better understanding of the pharmacology of 5-HT2 receptors, more specifically of 5-HT2B receptor, could help design new drugs devoid of cardiac side effects. We review here cellular mechanisms involved in valvular degeneration and regulated by serotonin stimulation, as well as the pharmacology of 5-HT2B receptor agonists that could provide new insight into VHD development.