Federal Project Grant Award Summary

The University of Texas Southwestern Medical Center received a $513,535 Project Grant award from the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853), effective June 1, 2026, through May 31, 2030. The award supports structure-guided discovery research aimed at developing potent small molecule positive allosteric modulators (PAMs) for the D2 dopamine receptor (DRD2). The research leverages cryo-electron microscopy (cryo-EM) structures of the activated DRD2 signaling complex to design the first drug-like PAM compounds capable of potentiating dopamine signaling, with potential applications as biological tools and future therapeutic leads for Parkinson's disease treatment.

The project delivers research products and findings that address a significant therapeutic gap in dopamine-targeted pharmacology. Rather than relying solely on orthosteric agonists that mimic dopamine, PAMs offer a complementary approach that acts synergistically with endogenous dopamine to restore physiologically appropriate signaling patterns in the brain. This structure-guided approach represents an innovation in GPCR (G protein-coupled receptor) drug discovery, as no DRD2 PAMs have previously advanced to preclinical or clinical evaluation. The research is positioned to generate both scientific knowledge regarding allosteric binding sites on DRD2 and drug-candidate compounds with potential to improve outcomes for the approximately 10 million Parkinson's disease patients worldwide.