Avoiding The Death Receptor

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-HT_2B, 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-HT_1B and of 5-HT_2B, 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 biology professor at Scripps Research Institute, La Jolla, Calif.; Bryan L. Roth, a pharmacology professor at the University of North Carolina; H. Eric Xu, director of the Center for Structural Biology & Drug Discovery at Van Andel Research Institute in Grand Rapids, Mich., and Hualiang Jiang, a professor at the Shanghai Institute of Materia Medica.

Reaction to the new work has been enthusiastic. “These are the first structures of the large 5-HT family, which is one of the most important classes in central nervous system disease,” observes Fiona Marshall, founder and chief scientific officer of drug discovery firm Heptares Therapeutics.

“This is major news for our field,” adds Kathryn A. Cunningham, a professor in the pharmacology and toxicology department at the University of Texas Medical Branch. “The structures were solved for the receptor-ligand cocrystals, which provides important insights into how the receptors work.”

The importance of selectivity was most infamously illustrated in the 1990s by the obesity treatment Fen-Phen (fenfluramine-phentermine). Both molecules targeted 5-HT receptors, but they weren’t selective enough. Unbeknown to scientists, they also bound to the death receptor, 5-HT_2B, triggering sometimes-fatal cardiovascular side-effects. Fen-Phen’s withdrawal from the market was the largest in history and cost its manufacturer, Wyeth, billions of dollars in damages.

From the structures and simulations, the group discovered that 5-HT_1B and 5-HT_2B contain similar main binding pockets. In addition, 5-HT_2B has a secondary binding pocket that is a good match for fenfluramine’s active metabolite. And that, they report, is enough to account for Fen-Phen’s adverse effect.