title: A Novel Class of Dopamine D4 Receptor Ligands Bearing an Imidazoline Nucleus.
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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.|Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Gianfabio
authors.initials: G
authors.lastname: Giorgioni
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Newman
authors.affiliation: Integrative Neurobiology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.affiliation: Integrative Neurobiology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Soto
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA.|Department of Chemistry & Biochemistry, Department of Biomedical & Translational Sciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, NJ, 08028, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keck
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy. fabio.delbello@unicam.it.
authors.forename: Fabio
authors.identifier: 0000-0001-6538-6029
authors.initials: F
authors.lastname: Del Bello
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D048288:Imidazolines; D008024:Ligands; D050638:Receptors, Dopamine D4
keywords: D4 receptor antagonists; dopamine; drug design; imidazolines; privileged structures