Experimental therapy targets PAH-driving serotonin receptor

VU6047534 reduced strain on the hearts of lab mice without brain side effects

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with VU6047534, an experimental therapy that blocks the activity of a specific type of serotonin receptor, reduced strain on the heart in a mouse model of pulmonary arterial hypertension (PAH) in a new study.

The study, “Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension,” was published in the Journal of the American College of Cardiology: Basic to Translational Science.

Serotonin is a signaling molecule that has many different roles throughout the body. It perhaps is best known for its activity in the brain, where it plays key roles in regulating mood. Serotonin acts by binding to protein receptors on the surface of cells, and there are several different types of serotonin receptors with specialized functions.

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Previous research has suggested that a specific serotonin receptor called 5-HT2B plays a key role in the development of PAH, so blocking this receptor theoretically could be a useful strategy to treat the disease.

The problem with this idea, however, is that blocking the activity of 5-HT2B may cause off-target neurological effects, so researchers would need to develop a therapy candidate that does not cross the blood-brain barrier — a semipermeable border that protects the brain against toxins in the blood.

Here, scientists in the U.S. described the development of a novel compound, dubbed VU6047534, that was designed to overcome this problem.

“We modified some existing [drugs that block 5-HT2B] to make them more specific to the receptors in the heart that we were focused on,” David Merryman, PhD, said in a press release. Merryman is senior author of the study and a professor at Vanderbilt University in Tennessee.

The researchers designed VU6047534 so that it would target the activity of 5-HT2B specifically without substantially affecting other serotonin receptors in the body. The molecule also was designed so that it cannot get into the brain.

‘A rare feat in drug development’

“I’m pleasantly surprised that we were able to engineer VU6047534 such that it stays out of the brain while we made it a much more selective compound that doesn’t hit the other serotonin receptors. It doesn’t show any binding to the other serotonin receptors, which is a rare feat in drug development,” Merryman said.

In lab tests, the researchers showed that VU6047534 specifically behaves as a partial agonist for 5-HT2B, meaning that at low concentrations the drug blocks the receptor’s activity, but at high concentrations the drug activates 5-HT2B. The researchers noted, however, that the concentrations needed for VU6047534 to activate 5-HT2B are much higher than would be realistically found in the body. So, for all intents and purposes, the therapy works to block 5-HT2B.

After synthesizing the novel molecule, the researchers tested it in a model of PAH induced by exposing mice to hypoxia (low oxygen levels) and a chemical called sugen 5416.

Treatment with VU6047534 reduced heart strain

In PAH, high blood pressure in the lung’s vessels puts strain on the right side of the heart, causing it to become enlarged. In the mouse model, treatment with VU6047534 led to reduced heart strain, as evidenced by smaller size of the right ventricle and lower right ventricular systolic pressure.

The therapy showed these effects both when it was given prior to the induction of PAH, and when it was administered to mice with established PAH.

“The 5-HT2B partial agonist VU6047534 is highly efficacious as a preventative treatment in preclinical mouse models of PAH, while also demonstrating interventional capacity as well,” the researchers concluded.

The team now is using VU6047534 as a basis for developing similar molecules to target 5-HT2B that may have pharmacological properties better suited for use as medication in people.

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