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

The high affinity dopamine D-4 receptor ligandAPH199and derivatives thereof exhibit bias toward the G(i) signalingpathway over & beta;-arrestin recruitment compared to quinpirole.Based on APH199, two novel groups of D-4 subtype selectiveligands were designed and evaluated, in which the original benzylphenylsemicarbazide substructure was replaced by either a biphenylmethylurea or a biphenyl urea moiety. Functional assays revealed a rangeof different bias profiles among the newly synthesized compounds,namely, with regard to efficacy, potency, and GRK2 dependency, inwhich bias factors range from 1 to over 300 and activation from 15%to over 98% compared to quinpirole. These observations demonstratethat within bias, an even more precise tuning toward a particularprofile is possible, which in a general sense couldbecome an important aspect in future drug development. Docking studiesenabled further insight into the role of the ECL2 and the EPB in theemergence of bias, thereby taking advantage of the diversity of functionallyselective D-4 agonists now available.