Researchers have designed new compounds that mimic those naturally used by the body to regulate blood pressure, paving way for a potential new class of drugs for hypertension.
The most promising of them may literally be the key to controlling hypertension, switching off the signalling pathways that lead to the deadly condition, researchers said.
Scientists from the University of California, San Diego studied the properties of the peptide called catestatin that binds nicotinic acetylcholine receptors found in the nervous system, and developed a pharmacophore model of its active centers.
They screened a library of compounds for molecules that might match this 3D "fingerprint". The scientists then took their in-silico findings and applied them to lab experiments, uncovering compounds that successfully lowered hypertension.
"This approach demonstrates the effectiveness of rational design of novel drug candidates," said lead author Igor F Tsigelny, a research scientist with the university's San Diego Supercomputer Center (SDSC).
"Our results suggest that analogs can be designed to match the action of catestatin, which the body uses to regulate blood pressure," said Daniel T O'Connor, a professor at the UC San Diego School of Medicine and senior author of the study.
"Those designer analogs could ultimately be used for treatment of hypertension or autonomic dysfunction," said O'Connor.
The research may lead to a new class of treatments for hypertension. Researchers targeted the hormone catestatin for therapeutic potential.
Catestatin acts as the gatekeeper for the secretion of catecholamines - hormones that are released into the blood during times of physical or emotional stress. A drug that mimics the action of catestatin would thus allow people to control the hormones that regulate blood pressure.
Researchers figured out which residues of catestatin are responsible for binding to the nicotinic receptor - similar to mapping how the ridges on a key fit into a lock.
They created a three-dimensional model of the most important binding centers - the pharmacophore model. Then they screened about 250,000 3D compound structures in the Open NCI Database to select ones that fit this fingerprint of active centers.
They discovered seven compounds that met the requirements, and tested those compounds in live cells to gauge their effects on catecholamines. Based on their findings, they tried one compound (TKO-10-18) on hypertensive mice, and showed that this compound produced the same anti-hypertensive effect as catestatin.
"Further refinement of our model should lead to the synthesis and development of a novel class of anti-hypertensive agents," she said.
The study was published in Bioorganic & Medicinal Chemistry.
