title: Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D(2)-like receptors.
abstract: Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt.
authors.forename: Ismail
authors.initials: I
authors.lastname: Salama
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D017448:Receptors, Dopamine D2; D006220:Haloperidol
keywords: Binding affinity; Bivalent ligands; D(2) receptor; D(3) receptor; D(4) receptor; Dopamine; GPCR dimers