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 D 1 , D 2 , D 3 , D 4 , and D 5 and divided into two sub-families, the D 1 -like sub-family (D 1 and D 5 ) and D 2 -like sub-family (D 2 , D 3 and D 4 ) based on pharmacological properties, amino acid homology, and genetic organization. Aberrant D 3 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 D 3 ligands, we have identified a novel series of 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides that are high affinity ligands for this receptor. Graphical Abstract