Featured Research

from universities, journals, and other organizations

New key to 'switching off' hypertension

Date:
July 22, 2013
Source:
University of California, San Diego
Summary:
Researchers have designed new compounds that mimic those naturally used by the body to regulate blood pressure. The most promising of them may literally be the key to controlling hypertension, switching off the signaling pathways that lead to the deadly condition.

Catestatin-mimic pharmacophore model. Pharmacophore centers correspond to hydrophobic residues Leu5, Phe7, and Phe14; and positively charged residues Arg8, Arg10, and Arg15. Green circles represent hydrophobes and aromatic/hydrophobic features, while dark-blue circles represent NCN+ groups/cations/H-bond donors. Ribbon diagram and three-dimensional residue structures belong to superimposed catestatin.
Credit: Valentina Kouznetsova, UC San Diego

A team of University of California, San Diego researchers has designed new compounds that mimic those naturally used by the body to regulate blood pressure. The most promising of them may literally be the key to controlling hypertension, switching off the signaling pathways that lead to the deadly condition.

Published online this month in Bioorganic & Medicinal Chemistry, the scientists 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 next 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), as well as the UC San Diego Moores Cancer Center and the Department of Neurosciences.

"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."

The research may lead to a new class of treatments for hypertension, a disease which affects about 76 million people, or about one in three adults, in the United States, according to the American Heart Association. Untreated, it damages the blood vessels and is a leading risk factor for kidney failure, heart attack, and stroke.

Despite being a common and lethal cardiovascular risk factor, hypertension remains only partially controlled by current antihypertensive medications, most of which have serious side effects. Specifically, the SDSC/UC San Diego 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.

Based on earlier studies of the structure of catestatin, O'Connor, Tsigelny, and their colleagues 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.

"Analysis of the catestatin molecule yielded a family of small organic compounds with preserved potency and pathway specificity," said Valentina Kouznetsova, PhD, an associate project scientist at SDSC and the UC San Diego Moores Cancer Center. "Further refinement of our model should lead to the synthesis and development of a novel class of antihypertensive agents."

Authors include SDSC's Tsigelny, O'Connor, and Kouznetsova, as well as Nilima Biswas and Sushil K. Mahata, of UC San Diego's Departments of Medicine and Pharmacology.


Story Source:

The above story is based on materials provided by University of California, San Diego. Note: Materials may be edited for content and length.


Journal Reference:

  1. Igor F. Tsigelny, Valentina L. Kouznetsova, Nilima Biswas, Sushil K. Mahata, Daniel T. O’Connor. Development of a pharmacophore model for the catecholamine release-inhibitory peptide catestatin: Virtual screening and functional testing identify novel small molecule therapeutics of hypertension. Bioorganic & Medicinal Chemistry, 2013; DOI: 10.1016/j.bmc.2013.07.008

Cite This Page:

University of California, San Diego. "New key to 'switching off' hypertension." ScienceDaily. ScienceDaily, 22 July 2013. <www.sciencedaily.com/releases/2013/07/130722152613.htm>.
University of California, San Diego. (2013, July 22). New key to 'switching off' hypertension. ScienceDaily. Retrieved September 3, 2014 from www.sciencedaily.com/releases/2013/07/130722152613.htm
University of California, San Diego. "New key to 'switching off' hypertension." ScienceDaily. www.sciencedaily.com/releases/2013/07/130722152613.htm (accessed September 3, 2014).

Share This



More Health & Medicine News

Wednesday, September 3, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Snack Attack: Study Says Action Movies Make You Snack More

Snack Attack: Study Says Action Movies Make You Snack More

Newsy (Sep. 2, 2014) You're more likely to gain weight while watching action flicks than you are watching other types of programming, says a new study published in JAMA. Video provided by Newsy
Powered by NewsLook.com
U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

Newsy (Sep. 2, 2014) The U.N. says the problem is two-fold — quarantine zones and travel restrictions are limiting the movement of both people and food. Video provided by Newsy
Powered by NewsLook.com
Doctors Fear They're Losing Battle Against Ebola

Doctors Fear They're Losing Battle Against Ebola

AP (Sep. 2, 2014) As a third American missionary is confirmed to have contracted Ebola in Liberia, doctors on the ground in West Africa fear they're losing the battle against the outbreak. (Sept. 2) Video provided by AP
Powered by NewsLook.com
Tech Giants Bet on 3D Headsets for Gaming, Healthcare

Tech Giants Bet on 3D Headsets for Gaming, Healthcare

AFP (Sep. 2, 2014) When Facebook acquired the virtual reality hardware developer Oculus VR in March for $2 billion, CEO Mark Zuckerberg hailed the firm's technology as "a new communication platform." Duration: 02:24 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins