Exploring Structural Determinants of Bias among D4 Subtype-Selective Dopamine Receptor Agonists

The high affinity dopamine D₄ receptor ligand APH199 and derivatives thereof exhibit bias toward the G_i signaling pathway over β-arrestin recruitment compared to quinpirole. Based on APH199, two novel groups of D₄ subtype selective ligands were designed and evaluated, in which the original benzyl phenylsemicarbazide substructure was replaced by either a biphenylmethyl urea or a biphenyl urea moiety. Functional assays revealed a range of different bias profiles among the newly synthesized compounds, namely, with regard to efficacy, potency, and GRK2 dependency, in which bias factors range from 1 to over 300 and activation from 15% to over 98% compared to quinpirole. These observations demonstrate that within bias, an even more precise tuning toward a particular profile is possible, which─in a general sense─could become an important aspect in future drug development. Docking studies enabled further insight into the role of the ECL2 and the EPB in the emergence of bias, thereby taking advantage of the diversity of functionally selective D₄ agonists now available.