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. [GRAPHICS] .