US researchers have designed new molecules that could be used as a starting point for developing drugs that “switch off” high blood pressure in the body.
The scientists first studied natural molecules that the body uses to control blood pressure, identified the parts that are actively involved in switching off the signaling that leads to hypertension, and then designed “analogs” of the natural compounds to do the same.
The work, which focuses on one natural compound in particular, is reported in the July 17th online issue of Bioorganic & Medicinal Chemistry.
Senior author Daniel O’Connor, a professor at the University of California San Diego (UCSD) School of Medicine, says in a statement:
“Our results suggest that analogs can be designed to match the action of catestatin, which the body uses to regulate blood pressure.
Those designer analogs could ultimately be used for treatment of hypertension or autonomic dysfunction.”
Catestatin is a natural hormone that acts as the gatekeeper for the secretion of catecholamines – hormones that are released into the bloodstream during times of physical or emotional stress.
A drug that mimics this action would thus help control the hormones that regulate blood pressure.
In the US, around a third of adults – over 70 million people – have high blood pressure, and according to a 2012 report from the Centers for Disease Control and Prevention (CDC), over half do not have their hypertension under control.
If not treated, high blood pressure damages blood vessels and raises the risk of kidney failure, heart attack and stroke.
Yet despite it being a common and sometimes deadly condition, current treatments for high blood pressure only partially control it, and most can sometimes produce serious side effects in some people.
To regulate blood pressure, catestatin binds to nicotinic acetylcholine receptors found in the nervous system.
In earlier studies, Daniel O’Connor and colleagues had already figured out which parts of catestatin bind to the receptor, rather like mapping how the various ridges on a key help open a lock.
In this latest study they studied these “ridges” and developed a three-dimensional chemical model of the most important binding centers.
They then used this 3D model to search a library of 250,000 compound structures for molecules with a similar “fingerprint,” tested them on live cells and uncovered some that successfully lowered hypertension.
In further experiments using live mice with high blood pressure, they found that one compound in particular, TKO-10-18, had the same antihypertensive effect as catestatin.
Lead author Igor Tsigelny, a research scientist with the UCSD’s San Diego Supercomputer Center (SDSC), says:
“This approach demonstrates the effectiveness of rational design of novel drug candidates.”
The team says with further refinement, the model should lead to a new class of drugs to treat high blood pressure.