Investigating substituted phenylacetamide ligands in the D₄R extended binding pocket

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Selective targeting of the dopamine D4 receptor (D4R) shows promise for treating cognitive and substance use disorders.
• Previous work developed A-412997, a D4R-selective partial agonist, providing a basis for further investigation.

Purpose of the Study:

• To explore ligand interactions within the secondary binding pocket of D4R.
• To synthesize and evaluate novel analogs of A-412997 with modified alkyl chains.

Main Methods:

• Synthesized a series of compounds with extended and cyclized alkyl chains on the phenylacetamide's benzyl ring.
• Tested compound affinity and selectivity using competition radioligand binding assays on D2R, D3R, and D4R.
• Utilized molecular modeling to investigate ligand-receptor interactions within the D4R binding pocket.

Main Results:

• Extending the alkyl chain beyond two carbons decreased D4R affinity and selectivity.
• Cyclizing the alkyl chain significantly enhanced D4R affinity.
• Cyclized compounds maintained high selectivity (over 120-fold) for D4R against D2R and D3R.
• Molecular modeling indicated favorable interactions of cyclized rings within the D4R binding pocket.

Conclusions:

• Modification of the alkyl chain through cyclization is a viable strategy to improve D4R ligand affinity and selectivity.
• These findings contribute to the development of novel therapeutics for conditions like ADHD, Alzheimer's disease, and substance use disorders.