title: Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter.
abstract: The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.
authors.affiliation: Department of Chemistry, Aarhus University, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Brinkø
authors.affiliation: Laboratory of Molecular Neurobiology, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Larsen
authors.affiliation: Department of Chemistry, Aarhus University, Denmark; inSPIN & iNANO Centres, Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Heidi
authors.initials: H
authors.lastname: Koldsø
authors.affiliation: Department of Chemistry, Aarhus University, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Besenbacher
authors.affiliation: Laboratory of Molecular Neurobiology, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Kolind
authors.affiliation: Department of Chemistry, Aarhus University, Denmark; inSPIN & iNANO Centres, Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schiøtt
authors.affiliation: Laboratory of Molecular Neurobiology, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: steffen.sinning@clin.au.dk.
authors.forename: Steffen
authors.initials: S
authors.lastname: Sinning
authors.affiliation: Department of Chemistry, Aarhus University, Denmark. Electronic address: hhj@chem.au.dk.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Jensen
mesh_terms: D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007099:Imipramine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009154:Mutation; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D007099:Imipramine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Antidepressants; Bivalent ligands; Depression; Serotonin; Sonogashira coupling; Transporter