Avoiding The Death Receptor

Abstract

Receptors for the neurotransmitter serotonin are distributed throughout nearly every organ system in the body, and they are the targets of drugs to treat innumerable problems, including depression, migraines, and obesity. Drug designers do their best to craft molecules that zero in on individual serotonin receptors (also known as 5-HTs). But at least 14 5-HT subtypes are known, and many drugs can bind more than one. That’s a problem. In particular, scientists want to avoid a subtype known as 5-HT2B, which is sometimes called the “death receptor” because it can lead to life-threatening cardiac side- effects if unintentionally activated. Help will come from new crystal structures of 5-HT1B and of 5-HT2B, each bound to the migraine drugs ergotamine and dihydroergotamine (Science, DOI: 10.1126/science.1232807 and DOI: 10.1126/science.1232808). The findings provide a blueprint for designing more selective 5-HT inhibitors. The team behind the structures includes Raymond C. Stevens, a chemistry and molecular ...