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

Dopamine (1) plays a key role in normal physiological pathways in both the central nervous system and the periphery. The physiological impact of this neurotransmitter is mediated through its interaction with family of G-protein-coupled receptors (GPCRs). These receptors are designated as D₁, D₂, D₃, D₄, and D₅ and divided into two sub-families, the D₁-like sub-family (D₁ and D₅) and D₂-like sub-family (D₂, D₃ and D₄) based on pharmacological properties, amino acid homology, and genetic organization. Aberrant D₃ activity has been linked to multiple diseases and conditions such as depression, schizophrenia, substance use disorder, inflammatory diseases, and Parkinson’s disease (PD). As part of our on-going program focused on the identification of novel D₃ ligands, we have identified a novel series of 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides that are high affinity ligands for this receptor. [Figure not available: see fulltext.]