Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D₃ receptor ligands

Substance use disorder remains a major, unmet medical need. Cocaine is one of the most commonly abused recreational drugs and in 2018, there were over 5.5 million cocaine users. There are no approved therapies for the treatment of cocaine use disorder, but the D₃ dopamine receptor has been identified as a potential therapeutic target. Our initial lead compound (6) is a potent D₃ ligand with a high level of selectivity for D₃ over D₂, but its solubility is low. We have identified a new series of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides (7) that are potent D₃ binders that have moderate to high selectivity for D₃ over D₂. Exemplary members of this series were also significantly more soluble than our initial lead compound (6). [Figure not available: see fulltext.]