Discovery could provide new approaches to treat metabolic disorders

July 16, 2017

In 2009, Burris and Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, identified a high affinity synthetic inverse agonist of this same pair of nuclear receptors. An inverse agonist, which binds to the same site as an agonist, induces the opposite action of an agonist of that receptor.

For this new study, Burris said they used that first discovery, a compound known as T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including ROR? and ROR??.

The one compound that stood out was SR1078, which displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general.

"Unexpectedly, we found that SR1078 functioned as a ROR agonist," Burris said. "When we treated cells with SR1078 we got a significant increase in ROR? transcription. Similarly, with ROR??, SR1078 treatment resulted in a stimulation of ROR?? dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so."

Source: Scripps Research Institute