A Novel Class of Dopamine D4Receptor Ligands Bearing an Imidazoline Nucleus

Valerio Mammoli, Alessandro Bonifazi, Diego Dal Ben, Mario Giannella, Gianfabio Giorgioni, Alessandro Piergentili, Maria Pigini, Wilma Quaglia, Ajiroghene Thomas, Amy H. Newman, Sergi Ferré, Marta Sanchez-Soto, Thomas M. Keck, Fabio Del Bello

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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 D4over D2and D3receptors. In functional assays, the 3-methoxy-substituted derivative, endowed with the highest D4affinity value, and its 3-hydroxy analogue behaved as partial agonists with low intrinsic efficacy and as competitive D4antagonists when tested in the presence of the D2-like receptor agonist quinpirole. Molecular docking analysis, performed using a homology model of the human D4receptor developed using the X-ray crystal structure of the antagonist-bound human D3receptor as a template, was in accordance with the binding results and provided useful information for the design of novel imidazoline D4receptor ligands based on this new scaffold.

Original languageEnglish (US)
Pages (from-to)1819-1828
Number of pages10
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Molecular Medicine
  • Biochemistry
  • Pharmacology
  • Organic Chemistry


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