Structure-guided discovery of positive allosteric modulators for the D2 dopamine receptor

/Abstract The goal of this project is to use atomic structures of the activated human D2 dopamine receptor (DRD2) to develop potent small molecule positive allosteric modulators (PAMs) of this G protein-coupled receptor (GPCR) as biological tools and future therapeutic lead compounds. Dopamine activation of DRD2 regulates movement, reward and cognition among other physiological functions, and attenuation of dopamine signaling through this receptor is an important contributor to Parkinson’s disease (PD) which affects approximately 10 million people worldwide. Current therapeutics targeting DRD2 include orthosteric agonists that mimic dopamine for PD, however dopamine replacement therapy is unable to fully restore the natural spatiotemporal patterns of dopamine signaling in the brain, leading to loss of efficacy over time and other side effects. A complementary approach to targeting the orthosteric pocket of DRD2 is using a positive allosteric modulator (PAM) to act synergistically with endogenous dopamine to restore physiologically appropriate dopamine signaling. Despite the central importance of DRD2 signaling and the potential therapeutic benefits of positive allosteric modulation, no DRD2 PAMs have advanced to in-vivo preclinical studies or clinical evaluation. Harnessing our experience in structure determination of the activated signaling complex of DRD2 with Gi, we propose to use cryo-EM structures of this complex with dopamine and candidate PAM compounds in Aim 1 to guide the discovery of the first potent and drug-like small molecule PAMs that can potentiate dopamine signaling through this GPCR. In the second Aim, we will use our discovery of the presence of a binding pocket analogous to PAM sites in other GPCRs, along with the binding mode of the high-affinity agonist bromocriptine, to rationally design small molecules that can bind to this site in the active state and increase dopamine’s affinity. In the third Aim, we will use an unbiased synthon-based virtual screen of billions of drug-like small molecules to discover new compounds that can bind to this putative PAM site. Our combination of strengths in GPCR structural biology, computational drug discovery, and synthetic and medicinal chemistry places us in a unique position to pioneer development of DRD2 PAMs as tool compounds that occupy a unique and untapped pharmacological space with future therapeutic potential in PD. Project Number: 1R01NS143214-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Daniel Rosenbaum (+1 co-PI) | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $513,535 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MBBC-V (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11318749