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. Epub 2024 Jun 7.

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.

MeSH terms

  • Animals
  • Computer-Aided Design*
  • Dopamine Antagonists / pharmacology
  • Drug Design
  • Humans
  • Neural Networks, Computer
  • Parkinson Disease / drug therapy
  • Quantitative Structure-Activity Relationship*
  • Receptors, Dopamine D4 / antagonists & inhibitors
  • Receptors, Dopamine D4 / metabolism
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology

Substances

  • Receptors, Dopamine D4
  • Spiro Compounds
  • Dopamine Antagonists