title: Loratadine and analogues: discovery and preliminary structure-activity relationship of inhibitors of the amino acid transporter B(0)AT2.
abstract: B(0)AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain, but little is otherwise known about its function. To identify inhibitors for this transporter, we screened a library of 3133 different bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B(0)AT2 with an IC50 of 4 μM while being less active or inactive against several other members of the SLC6 family. Reversible inhibition of B(0)AT2 was confirmed by electrophysiology. A series of loratadine analogues were synthesized to gain insight into the structure-activity relationships. Our studies provide the first chemical tool for B(0)AT2.
authors.affiliation: Max Planck Institute of Psychiatry , 80804 Munich, Germany.
authors.forename: Serena
authors.initials: S
authors.lastname: Cuboni
authors.forename: Christian
authors.initials: C
authors.lastname: Devigny
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Hoogeland
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pomplun
authors.forename: Barbara
authors.initials: B
authors.lastname: Hauger
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004594:Electrophysiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D017336:Loratadine / Q000031:analogs & derivatives*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018408:Patch-Clamp Techniques; D011969:Receptors, Histamine H1 / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D039563:Histamine H1 Antagonists, Non-Sedating; D009419:Nerve Tissue Proteins; D011969:Receptors, Histamine H1; C506212:SLC6A15 protein, human; D049452:Green Fluorescent Proteins; D017336:Loratadine