Morphine is still the most widely-used pain reliever, or analgesic, in people with severe pain, but chronic use can lead to addiction and negative side effects such as respiratory issues, constipation, or diarrhea.
In a previous study published in Science Signaling by Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai, researchers identified a therapeutic target called a GPCR heteromer, which is a protein complex that is made up of two opioid receptors called mu and delta. They also showed that the heteromer is abundant in the area of the brain that processes pain, and is the likely cause of morphine tolerance and side effects.
In the current study, Dr. Devi carried out high throughput screening in collaboration with researchers at the National Institutes of Health (NIH) to identify which small molecules might act on the signaling pathway associated with this protein complex. Researchers found one compound called CYM51010 that was as potent as morphine, but less likely to result in tolerance and negative side effects. Dr. Devi’s team is currently developing modified versions of this compound that may have potential as analgesics with reduced side effects.
“GPCR heteromers have been suggested to represent powerful targets for improved, novel therapeutics with reduced adverse effects in people with severe pain,” said Dr. Devi. “However, there are presently no chemical tools that allow us to investigate their role in vivo. Our work represents a promising step in this direction, providing results that pave the way towards a new understanding of the function and pharmacology of opioid receptor heteromers.”
Dr. Devi and her team are currently working with co-author Marta Filizola, PhD, Associate Professor of Structural and Chemical Biology at Mount Sinai, to learn how CYM51010 binds to the protein complex. Armed with this information, they hope to modify the compound to treat pain without the development of dependency. They also plan to restrict their benefit to the gastrointestinal system and treat diarrhea associated with irritable bowel disease that is unresponsive to existing therapies.
This study was supported by National Institute on Drug Abuse Grants R01-008863 and K05-019521.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of just 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
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