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ChemMedChem. 2016 Aug 19;11(16):1819-28. doi: 10.1002/cmdc.201600022. Epub 2016 Mar 15.

A Novel Class of Dopamine D4 Receptor Ligands Bearing an Imidazoline Nucleus.

Author information

1
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
2
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
3
Integrative Neurobiology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
4
Department of Chemistry & Biochemistry, Department of Biomedical & Translational Sciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, NJ, 08028, USA.
5
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy. fabio.delbello@unicam.it.

Abstract

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.

KEYWORDS:

D4 receptor antagonists; dopamine; drug design; imidazolines; privileged structures

PMID:
26990230
PMCID:
PMC4993638
DOI:
10.1002/cmdc.201600022
[Indexed for MEDLINE]
Free PMC Article

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