New molecule stops drug cravings in mice, with fewer side effects

May 28, 2020

DURHAM, N.C. -- Duke University researchers have developed a synthetic molecule that selectively dampen the physiological rewards of cocaine in mice. It also may represent a new class of drugs that could be more specific with fewer side effects than current medications.

In mice that were treated with the stimulant cocaine or methamphetamine, the new molecule was found to calm their drug-induced hyperactivity and interfere with the dopamine system's ability to change metabolism in the brain's rewards center.

In mice that were allowed to self-administer cocaine, the treatment slowed down their drug use in 20 minutes to an hour, and reduced the amount of drug they used by more than 80 percent, compared to a control group of mice.

The molecule, SBI-553, activates cell surface chemical receptors called G protein-coupled receptors or GPCRs, which are the target of more than 35% of all FDA-approved drugs. (The discovery and characterization of GPCRs earned the team's Duke colleague, Robert Lefkowitz, the 2012 Nobel Prize in chemistry.)

When a GPCR is activated by a signaling molecule, it transmits that signal to the inner portion of the cell via interaction with two intracellular proteins: G protein and beta-arrestin. Most GPCR drugs in use today indiscriminately activate both G protein and beta-arrestin, and sometimes activating both molecules withthe same GPCR can produce dramatically different physiological effects.

Drug developers have been trying to identify compounds that selectively activate one or the other because they have the potential to be safer drugs with fewer side effects.

In a paper appearing online May 28 in the journal Cell, the Duke researchers report the development of a new class of small molecules that may allow for just that - thereby separating the good effects from the bad.

"This kind of idea has been kicking around for 20 years or so," said senior author Marc Caron, the James B. Duke professor of Cell Biology in the School of Medicine. His work has focused on GPCR signaling involved in disorders like addiction, schizophrenia, Parkinson's Disease and depression.

For decades, researchers working on drug abuse and addiction have pursued molecules that would activate one specific GPCR called neurotensin receptor 1 (NTSR1) as a way to interrupt the actions of stimulants and treat cocaine and methamphetamine addictions.

Neurotensin is known to be involved in drug-seeking behavior and food intake in mice. "It regulates the brain's reward system and motivated behavior," said senior post-doctoral fellow Lauren Slosky, who is the lead author on the paper.

But so far, the drugs that activate NTSR1 have severe side effects for blood pressure, body temperature and motor coordination, because those are also controlled by NTSR1. "This was known, but nobody could do anything about it," Caron said.

In collaboration with the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, the Duke team screened 400,000 small molecule drugs to see if any of them could stimulate the NTSR1 beta-arrestin response.

One small molecule called SBI-553 that emerged from the screen acts at a previously unknown site on the NTSR1 and selectively activates the beta-arrestin without activating the G protein. SBI-553 can bind the NTSR1 at the same time as this receptor's natural activator, a peptide known as neurotensin, and it promotes neurotensin's ability to activate beta-arrestin while blocking its ability to activate the G protein.

"This type of activity isn't something we've seen before," said study co-author Lawrence Barak, an associate research professor who has studied GPCRs for decades and initiated the NTSR1 research program at Duke as well as the collaborative, large-scale screening effort.

Like conventional NTSR1 activators, SBI-553 was found to reduce the amount of cocaine the animals consumed and their associated drug-craving. But it did so without the usual side effects of decreased blood pressure and body temperature and motor coordination problems.

"The current findings suggest that the selective activation of the NTSR1 beta-arrestin response is sufficient to produce some of the anti-addiction effects attributed to the NTSR1, but not its effects on blood pressure and body temperature," Slosky said.

Because NTSR1 is a prototypical GPCR, molecules of this class can now be pursued for other receptors, Slosky said. "This kind of modulator may allow for the fine-tuning of receptor signaling."
-end-
The Duke team and their colleagues at Sanford Burnham were recently awarded a $3.58 million grant from National Institutes of Health (NIH) to develop SBI-553 for clinical trials and evaluate its effects on behaviors associated with opioid addiction.

This research was supported by the National Institutes of Health (F32DA043931, K99DA048970, 1K01AG041211, K08HL125905-01, R21/33DA038019, P30DA029925, R37MH073853.)

CITATION: "Beta-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors," Lauren Slosky, Yuski Bai, Krisztian Toth, Caroline Ray, Lauren Rochelle, Alexandra Badea, Rahul Chandrasekhar, Vladimir Pogorelov, Dennis Abraham, Namratha Atluri, Satyamaheshwar Peddibhotla, Michael Hedrick, Paul Hersberger, Patrick Maloney, Hong Yuan, Zibo Li, William Wetsel, Anthony Pinkerton, Lawrence Barak and Marc Caron. Cell, June 11, 2020. DOI: 10.1016/j.cell.2020.04.053

Duke University

Related Blood Pressure Articles from Brightsurf:

Children who take steroids at increased risk for diabetes, high blood pressure, blood clots
Children who take oral steroids to treat asthma or autoimmune diseases have an increased risk of diabetes, high blood pressure, and blood clots, according to Rutgers researchers.

High blood pressure treatment linked to less risk for drop in blood pressure upon standing
Treatment to lower blood pressure did not increase and may decrease the risk of extreme drops in blood pressure upon standing from a sitting position.

Changes in blood pressure control over 2 decades among US adults with high blood pressure
National survey data were used to examine how blood pressure control changed overall among U.S. adults with high blood pressure between 1999-2000 and 2017-2018 and by age, race, insurance type and access to health care.

Transient increase in blood pressure promotes some blood vessel growth
Blood vessels are the body's transportation system, carrying oxygen and nutrients to cells and whisking away waste.

Effect of reducing blood pressure medications on blood pressure control in older adults
Whether the amount of blood pressure medications taken by older adults could be reduced safely and without a significant change in short-term blood pressure control was the objective of this randomized clinical trial that included 534 adults 80 and older.

Brain blood flow sensor discovery could aid treatments for high blood pressure & dementia
A study led by researchers at UCL has discovered the mechanism that allows the brain to monitor its own blood supply, a finding in rats which may help to find new treatments for human conditions including hypertension (high blood pressure) and dementia.

Here's something that will raise your blood pressure
The apelin receptor (APJ) has been presumed to play an important role in the contraction of blood vessels involved in blood pressure regulation.

New strategy for treating high blood pressure
The key to treating blood pressure might lie in people who are 'resistant' to developing high blood pressure even when they eat high salt diets, shows new research published today in Experimental Physiology.

Arm cuff blood pressure measurements may fall short for predicting heart disease risk in some people with resistant high blood pressure
A measurement of central blood pressure in people with difficult-to-treat high blood pressure could help reduce risk of heart disease better than traditional arm cuff readings for some patients, according to preliminary research presented at the American Heart Association's Hypertension 2019 Scientific Sessions.

Heating pads may lower blood pressure in people with high blood pressure when lying down
In people with supine hypertension due to autonomic failure, a condition that increases blood pressure when lying down, overnight heat therapy significantly decreased systolic blood pressure compared to a placebo.

Read More: Blood Pressure News and Blood Pressure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.