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A Novel Class of Dopamine D4 Receptor Ligands Bearing an Imidazoline Nucleus.
- Source :
-
ChemMedChem [ChemMedChem] 2016 Aug 19; Vol. 11 (16), pp. 1819-28. Date of Electronic Publication: 2016 Mar 15. - Publication Year :
- 2016
-
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.<br /> (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Binding Sites drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Partial Agonism
HEK293 Cells
Humans
Imidazolines chemical synthesis
Ligands
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Imidazolines chemistry
Imidazolines pharmacology
Receptors, Dopamine D4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 11
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 26990230
- Full Text :
- https://doi.org/10.1002/cmdc.201600022