Investigation of Novel Primary and Secondary Pharmacophores and 3‑Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D₃ Receptor Antagonists and Partial Agonists

Dopamine D₃ receptors (D₃R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)­butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D₃R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D₃R binding affinity (K_i = 0.756 nM) and was 327-fold selective for D₃R over D₂R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)­phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D₃R selectivity as well as drug-like features required for development as pharmacotherapeutics.