Targeting the 5-HT system: Potential side effects

Targeting the serotonin (5-HT) system is no simple task: there are at least 15 5-HT receptors, in addition to a number of transporters and metabolizing enzymes. Multiple 5-HT receptor variants exist due to genetic variations and/or post translational modifications, splice variants or editing variants. Some receptors may form homo and heteromers. The 5-HT system is targeted by multiple drugs to treat a variety of diseases. Given the homology amongst the 5-HT and neighbouring receptor classes, only few drugs are actually selective for a single target. In fact, many 5-HT drugs act on a combination of targets, i.e. several receptors and/or transporters or enzymes. For instance, a number of antidepressants or antipsychotics act on 5-HT and other transmitter systems. Recently developed drugs may show target selectivity by design, based on the current state of knowledge, whereas many older compounds hit multiple targets since they were developed using phenotypic screens, as was done well into the 1980's. Ergot analogues, antipsychotics or antidepressants, fall into this category. As our knowledge developed over the last 25-30 years, some targets have very well-defined liabilities: for instance, 5HT_2B or 5-HT_2A receptor agonists, will produce valvulopathies or hallucinations, respectively, whereas 5-HT₃ receptor antagonists, may lead to constipation. This short review will be limited in scope as there are multiple targets and even more compounds to discuss.

Keywords: 5-HT; 5-HT receptors; 5-HT syndrome; 5-Hydroxytrypatmine; Agranulocytosis; Constipation; Hallucinations; Ischemic heart disease; Neurotoxicity; Pulmonary hypertension; SNRIs ergotism; SSRIs; Serotonin; Transporter; Valvulopathies.