Investigating substituted phenylacetamide ligands in the D4R extended binding pocket

Preclinical studies indicate that selective targeting of D4R may improve behavioral and cognitive outcomes in animal models relevant to cognitive disorders, like ADHD and Alzheimer’s disease, and substance use disorders (SUDs). In this study, we extend upon prior development of analogs of A-412997, a D4R-selective partial agonist, by exploring ligand interactions within the secondary binding pocket. We modified the alkyl chain on the phenylacetamide’s benzyl ring by extending and cyclizing the alkyl chain. A series of compounds were synthesized and tested using competition radioligand binding assays on D2R, D3R, and D4R, using [3H]N-methylspiperone as the competing radioligand. Herein, we report that while increasing the chain length beyond two carbons reduced D4R affinity and selectivity, cyclizing the alkyl chain enhanced D4R affinity and maintained selectivity over D2R and D3R by 120-fold or more. Molecular modeling results suggest that the cyclized rings engage in more favorable interactions within the D4R binding pocket.