Sony Pixel Power calrec Sony

November 22, 2021

23/11/2021

Search for safer pain relief advances with new engineered compounds Chronic use of most opioids causes tolerance; the new compounds avoid this and other unwanted qualities.

November 22, 2021

JUPITER, FL Scientists at Scripps Research in Florida have created a collection of new pain-relieving compounds that, like morphine and other drugs, provide relief via activation of opioid receptors, but without inducing many dangerous and unwanted side-effects that have driven opioid-related overdose and deaths.

Writing Nov. 22 in the journal the Proceedings of the National Academies of Sciences, biochemist Laura Bohn, PhD, and colleagues describe a compound called SR-17018, which activates the same pain-relieving receptor as opioid drugs including morphine, oxycodone and fentanyl; however it binds to opioid receptors in a different way from those drugs, leaving the opioid receptor open and available to the body's own natural pain-relieving substances, apparently augmenting pain relief. In a study published earlier this year (Pantouli et al., 2021, Neuropharmacolgy), the group showed that the compound performed particularly well in mouse studies of chemotherapy-induced neuropathic pain, the scientists write.

In the current report, the authors have made strides in understanding why these drugs seem so different.

We demonstrate that these compounds bind to a different site on the receptor than a typical opioid. Because of that, they seem to leave the receptor on and yet still receptive to endogenous opioids, says Bohn, who chairs the Scripps Research Department of Molecular Medicine in Jupiter, Florida. In neuropathy pain, we show they are far superior to morphine and oxycodone; moreover, SR-17018 does not decrease breathing.

The authors also described a related compound that, being more potent, induces respiratory suppression, but at higher doses than are needed to relieve pain. Importantly for safety, this compound, SR-14968, proved responsive to overdose rescue medication naloxone, when given at doses high enough to suppress breathing.

Perhaps most importantly for people with severe chronic pain, SR-17018 showed an ability to provide sustained pain relief over time without development of tolerance, the problem of reduced efficacy over time that requires increased doses, increasing danger of overdose.

The paper's first author, Edward L. Stahl, notes that the new compounds are referred to as biased agonists, because they activate the mu opioid receptor in a way that preferentially engages one of its signaling pathways, the one that provides pain relief, over other pathways such as those that lead to suppressed breathing.

The compound SR-17018 is the first biased agonist of the mu opioid receptor that does not lead to tolerance with chronic use, says Stahl, a senior staff scientist in the Bohn lab. This is a desirable feature for potential use in the context of chronic, severe pain.

The new compounds were engineered to avoid the beta-arrestin signaling cascade that leads to opioids' dangerous and unwanted traits, including respiratory suppression, a cause of overdose, and constipation, he adds.

Opioid medications remain a go-to treatment for severe pain, whether it's from surgery, a sudden injury, or nerve damage. But as opioid addiction and overdose deaths reach new highs in the United States, the need for safer ways to treat acute pain has grown more urgent, Bohn says.

In work spanning more than two decades, Bohn and her team have demonstrated the feasibility of untangling the pain-relieving properties of opioids from their negative traits. Her work has not only broadened understanding of how opioid receptors work to direct multiple physiological responses, it has pointed the field toward potentially safer options for providing relief from severe pain.

Bohn's research group has engineered multiple compounds which, in mouse studies, diminish activation of beta-arrestin signaling. Additional problems of opioids continue to pose challenges, including dependance, or addiction. The fact that SR-17018 avoids tolerance with chronic use is good news, Bohn says. Also good news is how it wears off, she adds.

The compound showed a nice, slow tapering. That, in itself, may help curb some of the dependence problems. A drug like morphine provides a quick rush then a quick clear, and you need the rush again.

Going forward, the team is continuing to refine and test the compounds so that they could eventually be tested in a clinical setting.

Severe and chronic pain associated with surgery, nerve damage, and trauma require strong pain relief, Bohn says. Safer solutions are needed. We believe these new compounds are a big step in the right direction.

In addition to Bohn and Stahl, the co-authors of the paper, G protein-signaling biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists, are Cullen L. Schmid, Agnes Acevedo-Canabal, Cai Read, Travis Grim, Nicole Kennedy and Thomas D. Bannister.

Grants from the National Institutes on Drug Abuse supported the work, including R01DA038964, R01DA033073,and F32DA052124.

Molecular Medicine Bohn, Laura Addiction
LINK: https://www.scripps.edu/news-and-events/press-room/2021/20211122-bohn-...
See more stories from scripps

More from Scripps

13/03/2024

March 13, 2024

New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of...

29/02/2024

February 29, 2024

Scripps Research scientists reveal how first cells could have formed on Earth New phospholipid discovery brings researchers closer to understanding how primordi...

29/02/2024

February 28, 2024

How molecular handedness emerged in early biology Scripps Research chemists fill a major gap in origin-of-life theories. February 28, 2024 LA JOLLA, CA Mole...

22/02/2024

February 21, 2024

Snaking toward a universal antivenom Scripps Research scientists discovered antibodies that protect against a host of lethal snake venoms. February 21, 2024 ...

06/02/2024

February 06, 2024

Calibr-Skaggs announces expansion of option and license agreement with AbbVie to develop novel cell therapies for solid tumors and autoimmune diseases AbbVie...

26/01/2024

January 25, 2024

Re-energizing mitochondria to treat Alzheimer's disease Scripps Research team restored neuron-to-neuron connections in human cells. January 25, 2024 LA JO...

24/01/2024

January 04, 2024

100 years of Science Changing Life: Scripps Research celebrates a century of transforming human health For the last century, institute leaders and renowned scie...

23/01/2024

January 23, 2024

New technology lets researchers track brain cells' off switches The method could shed light on what goes awry in numerous brain conditions when neurons ar...

09/01/2024

January 08, 2024

Three decades of giving: Announcing the Calibr-Skaggs Institute for Innovative Medicines The ALSAM Foundation, founded by the Skaggs family, provides lasting g...

04/01/2024

January 03, 2024

Life science entrepreneur Gene Lay joins Scripps Research Board of Directors Lay, founder of the global biotech company BioLegend, brings invaluable experience ...

21/12/2023

December 20, 2023

Taming a plant-derived toxin Scripps Research team modifies the traditional poison picrotoxinin for potential neurological drugs and anti-parasite treatments. ...

19/12/2023

December 18, 2023

Scripps Research Executive Vice President Eric Topol gives TED talk on transformative power of AI in medicine Topol provides an overview of how AI models can i...

13/12/2023

December 12, 2023

New AI-powered algorithm could better assess people's risk of common heart condition Early detection of atrial fibrillation can reduce the risk of stroke an...

07/12/2023

December 06, 2023

Nanoparticle flu vaccine design shows promise in early tests Scripps Research-designed vaccine could provide broad, enduring protection against influenza A str...

16/11/2023

November 15, 2023

Numerous Scripps Research scientists named Highly Cited Researchers Clarivate's annual, global list represents researchers who have demonstrated significant...

07/11/2023

November 06, 2023

Multiple sclerosis drug invented at Scripps Research slows long-term devastating disease progression Late-breaking data reinforces the effectiveness and safety ...

05/10/2023

October 04, 2023

Keren Lasker named a 2023 Moore Inventor Fellow The prestigious award will support Lasker's inventive research in membraneless organelles and their applica...

22/09/2023

September 21, 2023

Michael Bollong named a 2023 Amgen Young Investigator The prestigious award will support Bollong's research identifying new molecular targets and therapeuti...

09/09/2023

September 08, 2023

Philip Dawson receives 2024 American Chemical Society National Award Dawson is honored with the Arthur C. Cope Late Careers Scholar Award for his foundational c...

07/09/2023

September 06, 2023

Scripps Research chemists devise a method for C-H activation of alcohols The method represents a new toolkit for making drugs and other compounds. September 06...

31/08/2023

August 30, 2023

Scripps Research receives $1.5M to surveil infectious disease threats in wastewater Bill & Melinda Gates Foundation award to support the development of multi-pa...

16/08/2023

August 16, 2023

How cold temperatures trigger the brain to boost appetite Scripps Research scientists' discovery could lead to new weight loss and metabolic health treatmen...

08/08/2023

August 07, 2023

Human antibody that targets carfentanil, fentanyl and related opioids reverses overdose effects in preclinical study Scripps Research-developed antibody therapy...

04/08/2023

August 03, 2023

How sensory neurons impact the gut Scripps Research scientists show that the receptor PIEZO2 in sensory neurons controls gut motility and transit time, which a...

26/07/2023

July 26, 2023

AbbVie and Calibr Expand Strategic Collaboration to Advance Several Preclinical and Early-stage Clinical Assets The expanded strategic collaboration will advan...

23/07/2023

July 21, 2023

Scripps Research scientists develop AI-based tracking and early-warning system for viral pandemics Machine-learning system effectively predicts emergence of pro...

19/07/2023

July 19, 2023

Monitoring T cells may allow prevention of type 1 diabetes Scripps Research study shows that analyzing T cells in blood samples could be used to select at-risk ...

19/07/2023

July 18, 2023

Scripps Research mourns passing of leading organic chemist Albert Eschenmoser Eschenmoser pioneered key reactions in synthetic chemistry and shaped the understa...

15/06/2023

June 14, 2023

Scripps Research awarded $46.8 million by NIH to promote human health through innovative translational science and training The Translational Institute is harne...

13/06/2023

June 13, 2023

Scripps Research's Danielle Grotjahn named 2023 Pew Scholar in the Biomedical Sciences The award will support Grotjahn's study of how cells assemble the...

31/05/2023

May 31, 2023

Crossing the ring: new method enables C-H activation across saturated carbocycles Scripps Research chemists add another powerful tool to their molecular editin...

24/05/2023

May 23, 2023

Scripps Research develops behind-the-scenes tool for better biomedical data discovery The new resource makes datasets more discoverable for life science communi...

19/05/2023

May 15, 2023

Scripps Research neuroscientist Hollis Cline elected to American Academy of Arts and Sciences Cline is recognized for her discoveries about the role of sensory ...

19/05/2023

May 18, 2023

Scripps Research's Skaggs Graduate School awards doctoral degrees to 31st graduating class Commencement ceremony will be livestreamed via Zoom and on instit...

13/05/2023

May 12, 2023

A better route to benzocyclobutenes, sought-after building blocks for drugs Scripps Research chemists devise a new, C-H activation-based method for the synthesi...

09/05/2023

May 08, 2023

Renowned Scripps Research professor Jeffery Kelly elected to National Academy of Sciences Kelly's groundbreaking work on protein misfolding has led to thera...

28/04/2023

April 27, 2023

Mirror-image molecules pave new path for cancer drug discovery By comparing how mirror image versions of small molecules impact clusters of proteins, Scripps R...

22/04/2023

April 21, 2023

How alcohol consumption contributes to chronic pain A Scripps Research team showed how both alcohol intake and alcohol withdrawal can lead to increased pain and...

21/04/2023

April 20, 2023

Xin Jin receives dual awards to study autism risk genes in neurodevelopment Major grants from the National Institutes of Health and California Institute for Reg...

20/04/2023

April 19, 2023

Trim the sugar: New HIV vaccine design improves immune response Scripps Research vaccine candidate headed for clinical trials. April 19, 2023 LA JOLLA, CA A...

18/04/2023

April 17, 2023

Therapeutic can seek and destroy potent opioid to treat overdoses Scripps Research chemists developed a new biologic to work against the synthetic opioid carfen...

07/03/2023

March 06, 2023

How heavy alcohol consumption increases brain inflammation The findings by a Scripps Research team point toward a potential new drug target for treating alcohol...

02/03/2023

March 01, 2023

Scientists find human antibodies that can block multiple coronaviruses including SARS-CoV-2 Results from a Scripps Research and UNC team pave the way for a vacc...

28/02/2023

February 28, 2023

$10 million grant funds Scripps Research Alcohol Research Center through its 50th year The five-year grant supports research into the neurobiology of alcohol us...

28/02/2023

February 27, 2023

Immune system drug shows promise in treating alcohol use disorder, a Scripps Research clinical trial reports Scientists at Scripps Research found that apremilas...

23/02/2023

February 16, 2023

Chemically poisoned protein acts as a molecular switch to spur cancer formation The discovery triggered development of a new potential drug to eliminate tumor...

23/02/2023

February 23, 2023

Two new papers demonstrate use of Outbreak.info as one-stop online source for COVID data Scripps Research scientists highlight the need for continued monitorin...

15/02/2023

February 15, 2023

Calibr and Bill & Melinda Gates Medical Research Institute announce licensing agreement for novel candidate tuberculosis treatment compound Calibr transitions i...

08/02/2023

February 07, 2023

Scripps Research Professor Jeffery Kelly awarded 2023 Wolf Prize in Chemistry Kelly receives the prestigious award for his seminal discoveries in protein-foldin...

31/01/2023

January 30, 2023

Experimental anti-depression drug may also be useful in treating alcohol use disorder Investigational, clinical-stage antidepressant MAP4343 shown to reduce alc...