title: Development of potent dopamine-norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template.
abstract: Current therapy of depression is less than ideal with remission rates of only 25-35% and response rates of 45-60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (Ki (SERT); 0.71 and 2.68nM, respectively) or a potent DNRI profile for compounds 6b and 6h (Ki (DAT/NET); 8.94/4.76 and 13/7.37nM, respectively). Compounds 4g-4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors.forename: Soumava
authors.initials: S
authors.lastname: Santra
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors.forename: Horrick
authors.initials: H
authors.lastname: Sharma
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors.forename: Seenuvasan
authors.initials: S
authors.lastname: Vedachalam
authors.affiliation: New York University, Department of Psychiatry, New York, NY 10016, United States.
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.affiliation: New York University, Department of Psychiatry, New York, NY 10016, United States; New York University, Department of Pharmacology, New York, NY 10016, United States.
authors.forename: Maarten
authors.initials: M
authors.lastname: Reith
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States. Electronic address: adutta@wayne.edu.
authors.forename: Aloke
authors.initials: A
authors.lastname: Dutta
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D001596:Benzylamines; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans; D050486:Serotonin Plasma Membrane Transport Proteins; D004298:Dopamine; D009638:Norepinephrine
keywords: Dopamine transporter; Major depressive disorder; Norepinephrine transporters; Selective serotonin reuptake inhibitors; Serotonin transporter; Serotonin/norepinephrine reuptake inhibitors; Structure activity relationship; Triple reuptake inhibitor