2. Academic Validation
  3. Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists

Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists

  • ACS Chem Neurosci. 2024 Jun 19;15(12):2396-2407. doi: 10.1021/acschemneuro.4c00086.
Caleb A H Jones 1 2 3,  Benjamin P Brown 3 4 5,  Daniel C Schultz 1 2 3,  Julie Engers 1 2 3,  Valerie M Kramlinger 1 2 3,  Jens Meiler 3 4 5 6,  Craig W Lindsley 1 2 3
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Center for Applied AI in Protein Dynamics, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Institute for Drug Discovery, Leipzig University Medical School, Leipzig SAC 04103, Germany.
PMID: 38847395 DOI: 10.1021/acschemneuro.4c00086
Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective Dopamine Receptor subtype 4 (D4R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D4R antagonists. However, developing selective D4R antagonists suitable for clinical translation remains a challenge.

Keywords

D4R antagonism; Parkinson’s disease; dopamine receptors.

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