title: Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Synthesis, biological characterization, and development of a pharmacophore model.
abstract: In this study we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The model revealed features important for inhibitors to exhibit a balanced activity against dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In particular, a 'folded' conformation was found common to the active pyran compounds in the training set and was crucial to triple uptake inhibitory activity. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. The present work has also resulted in the discovery of a new series of asymmetric tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and 42 exhibited moderate TUI activity. Interestingly, the highest TUI activity by lead tetrahydrofuran compounds for example, 41 and 42, was exhibited in a stereochemical preference similar to pyran TUI for example, D-161.
authors: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors: Horrick
authors: H
authors: Sharma
authors: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors: Soumava
authors: S
authors: Santra
authors: Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI 48202, United States.
authors: Joy
authors: J
authors: Debnath
authors: New York University, Department of Psychiatry, New York, NY 10016, United States.
authors: Tamara
authors: T
authors: Antonio
authors: 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: Maarten
authors: M
authors: Reith
authors: 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: Aloke
authors: A
authors: Dutta
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D032701:Biomimetics; D001921:Brain / Q000378:metabolism; D019295:Computational Biology; D003863:Depression / Q000188:drug therapy / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008968:Molecular Conformation; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D011714:Pyrans
keywords: Antidepressants; Asymmetric synthesis; Computational analysis; DAT; Depression; MAO; NET; Pharmacophore model; SAR; SERT; SNRI; SSRI; TCA; TUI; Triple uptake inhibitors; dopamine transporter; monoamine oxidase inhibitors; norepinephrine transporters; selective serotonin reuptake inhibitors; serotonin transporter; serotonin/norepinephrine reuptake inhibitors; structure–activity relationship; tricyclic antidepressants; triple uptake inhibitor