A Novel Class of Dopamine D 4 Receptor Ligands Bearing an Imidazoline Nucleus

Over the years, the 2‐substituted imidazoline nucleus has been demonstrated to be a bioversatile structural motif. In this study, novel imidazoline derivatives bearing a 3‐ and/or 4‐hydroxy‐ or methoxy‐substituted phenyl ring, linked by an ethylene bridge to position 2 of an N ‐benzyl‐ or N ‐phenethyl‐substituted imidazoline nucleus, were prepared and studied against D 2 ‐like receptor subtypes. Binding studies highlighted that a set of N ‐phenethylimidazoline compounds are selective for D 4 over D 2 and D 3 receptors. In functional assays, the 3‐methoxy‐substituted derivative, endowed with the highest D 4 affinity value, and its 3‐hydroxy analogue behaved as partial agonists with low intrinsic efficacy and as competitive D 4 antagonists when tested in the presence of the D 2 ‐like receptor agonist quinpirole. Molecular docking analysis, performed using a homology model of the human D 4 receptor developed using the X‐ray crystal structure of the antagonist‐bound human D 3 receptor as a template, was in accordance with the binding results and provided useful information for the design of novel imidazoline D 4 receptor ligands based on this new scaffold.