A Novel Class of Dopamine D4 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 D2 -like receptor subtypes. Binding studies highlighted that a set of N-phenethylimidazoline compounds are selective for D4 over D2 and D3 receptors. In functional assays, the 3-methoxy-substituted derivative, endowed with the highest D4 affinity value, and its 3-hydroxy analogue behaved as partial agonists with low intrinsic efficacy and as competitive D4 antagonists when tested in the presence of the D2 -like receptor agonist quinpirole. Molecular docking analysis, performed using a homology model of the human D4 receptor developed using the X-ray crystal structure of the antagonist-bound human D3 receptor as a template, was in accordance with the binding results and provided useful information for the design of novel imidazoline D4 receptor ligands based on this new scaffold.