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A Novel Class of Dopamine D 4 Receptor Ligands Bearing an Imidazoline Nucleus
Author(s) -
Mammoli Valerio,
Bonifazi Alessandro,
Dal Ben Diego,
Giannella Mario,
Giorgioni Gianfabio,
Piergentili Alessandro,
Pigini Maria,
Quaglia Wilma,
Thomas Ajiroghene,
Newman Amy H.,
Ferré Sergi,
SanchezSoto Marta,
Keck Thomas M.,
Del Bello Fabio
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600022
Subject(s) - imidazoline receptor , chemistry , agonist , stereochemistry , docking (animal) , receptor , homology modeling , quinpirole , nucleus , biochemistry , pharmacology , biology , enzyme , neuroscience , nursing , medicine
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.