학술논문
Synthesis of spiro-2,6-dioxopiperazine and spiro-2,6-dioxopyrazine scaffolds using amino acids in a three-component reaction to generate potential Sigma-1 (σ 1 ) receptor selective ligands.
Document Type
Academic Journal
Author
Uprety R; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Váradi A; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Allaoa A; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Redel-Traub GN; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Palmer TC; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Feinberg EN; Biophysics Program and Department of Chemistry, Stanford University, Stanford, CA, USA.; Ferris AC; Bioengineering Department, Stanford University, Stanford, CA, USA.; Pande VS; Biophysics Program and Department of Chemistry, Stanford University, Stanford, CA, USA.; Pasternak GW; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.; Majumdar S; Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA; Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. Electronic address: susrutam@email.wustl.edu.
Source
Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ 1 ) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ 1 receptor have shown that it resides in the same binding site that was occupied by the ligand 4-IBP used to obtain a crystal structure of the human sigma-1 (σ 1 ) receptor.
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)