Development of pyrimidone D1 dopamine receptor positive allosteric modulators

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Drug Discovery

Background:

• Potentiation of dopamine receptor D1 (D1R) signaling is a promising therapeutic strategy for neurocognitive disorders.
• MLS1082 is a novel pyrimidone-based positive allosteric modulator of D1-like dopamine receptors.

Purpose of the Study:

• To investigate the structure-activity relationships of MLS1082 by modifying its N-aryl and C-alkyl groups.
• To identify novel analogues with enhanced D1R potentiation capabilities.

Main Methods:

• Synthesis of 24 new pyrimidone-based analogues of MLS1082.
• Characterization of the analogues' ability to potentiate dopamine signaling at D1R and D5R.
• Structure-activity relationship analysis for aryl and alkyl modifications.

Main Results:

• Identified key structure-activity relationship trends for N-aryl and C-alkyl groups.
• Several analogues exhibited improved D1R potentiation compared to the parent compound.
• The most effective analogues amplified dopamine-mediated D1R signaling by approximately 8-fold.

Conclusions:

• Structural modifications of the pyrimidone core significantly impact D1R allosteric modulation.
• These findings provide valuable insights into the design of potent D1R positive allosteric modulators for neurocognitive disorders.