TY - JOUR
T1 - A Novel Class of Dopamine D4Receptor Ligands Bearing an Imidazoline Nucleus
AU - Mammoli, Valerio
AU - Bonifazi, Alessandro
AU - Dal Ben, Diego
AU - Giannella, Mario
AU - Giorgioni, Gianfabio
AU - Piergentili, Alessandro
AU - Pigini, Maria
AU - Quaglia, Wilma
AU - Thomas, Ajiroghene
AU - Newman, Amy H.
AU - Ferré, Sergi
AU - Sanchez-Soto, Marta
AU - Keck, Thomas M.
AU - Del Bello, Fabio
N1 - Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1002/cmdc.201600022
DO - 10.1002/cmdc.201600022
M3 - Article
C2 - 26990230
AN - SCOPUS:84983340565
SN - 1860-7179
SP - 1819
EP - 1828
JO - ChemMedChem
JF - ChemMedChem
ER -