RTI International's JDTic Helps Scientists Uncover Structure of the Kappa Opioid Receptor

Finding may accelerate development of new medicine for pain, depression, substance abuse disorder, other conditions

Graphic rendering of JDTic kappa opioid receptor

RESEARCH TRIANGLE PARK, N.C. — A research team led by scientists at The Scripps Research Institute recently used JDTic, a compound synthesized by RTI International and donated to the National Institute on Drug Abuse (NIDA) Drug Supply Program, to determine the 3-D atomic structure of the kappa opioid receptor (κ-OR), a receptor in human brains that moderates pleasure, pain, addiction, depression, psychosis and related conditions.

Their finding, published in the March 21 issue of the journal Nature, creates a pathway for the design of safer and more effective opioid drugs to treat addiction, depression and other conditions. The research team included scientists from the University of North Carolina at Chapel Hill, RTI International and Virginia Commonwealth University.

Until now, scientists had been unable to determine the exact structure of κ-OR. This receptor is one of three known opioid receptors (kappa, mu and delta) and the closely related nociception (ORL-1) receptor in the human brain. K-OR is the receptor targeted by the highly potent hallucinogen salvinorin A, the active ingredient in a widely abused hallucinogenic plant.

"Understanding the structure of κ-OR provides a long awaited molecular framework for understanding opioid drug action," said Ivy Carroll, Ph.D., a distinguished fellow at RTI International and one of the co-authors of the study. "This discovery offers valuable new opportunities for the structure-based discovery of new drugs with ideal pharmacological properties."

Using the κ-OR structure, along with other information, scientists may now be able to develop drugs that target the receptor to limit negative side effects of opioid drugs used medicinally, such as morphine and codeine. This could lead to a new generation of therapeutic drugs to treat addiction, chronic pain, anxiety, depression and other conditions.

To determine the structure of the κ-OR, the research team used a high-resolution 3-D image of κ-OR bound to JDTic, a compound that keeps the receptor in an inactive state. The researchers mapped the points of contact between JDTic and the κ-OR to see how the two fit together.

"JDTic fits the receptor like a hand in a glove," said Wayne Mascarella, senior chemist in RTI International's Organic and Medicinal Chemistry unit and a co-author on the study. "This close fit, combined with other information about JDTic, allowed the research team for the first time to accurately determine the map of κ-OR's atomic structure."

In studies using animal models, JDTic has shown that kappa opioid antagonists have potential for treating depression, anxiety, and cocaine and nicotine addiction.

Armed with the structure of the κ-OR, scientists at RTI International , academia and drug companies will be able to improve existing kappa-targeting compounds, such as JDTic, and design entirely new ones.

"This finding is going to have a major impact on understanding the fundamental principles of opioid receptor recognition and evolution," said Raymond Stevens, Ph.D., a professor at The Scripps Research Institute.

The study was supported by NIDA, the National Institute of General Medical Sciences and the National Institute of Mental Health, all components of the National Institutes of Health.