title: Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.
abstract: Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, United States.
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, United States.
authors.forename: Soumava
authors.initials: S
authors.lastname: Santra
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, United States.
authors.forename: Horrick
authors.initials: H
authors.lastname: Sharma
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, United States.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Voshavar
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.affiliation: University of Michigan, Department of Pharmacology and Chemistry, Ann Arbor, MI, United States.
authors.forename: Omar
authors.initials: O
authors.lastname: Mabrouk
authors.affiliation: New York University, Department of Psychiatry, New York, NY, United States.
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.affiliation: New York University, Department of Psychiatry, New York, NY, United States; New York University, Department of Biochemistry and Molecular Pharmacology, New York, NY, United States.
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
mesh_terms: D000284:Administration, Oral; D000606:Amino Sugars / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001596:Benzylamines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013550:Swimming
chemical_list: D000606:Amino Sugars; D000928:Antidepressive Agents; D001596:Benzylamines; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C000599405:2-(bis(4-fluorophenyl)methyl)-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol