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Eur J Med Chem. 2018 Dec 22;164:241-251. doi: 10.1016/j.ejmech.2018.12.048. [Epub ahead of print]

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 (σ1) receptor selective ligands.

Author information

1
Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, NY, USA.
2
Biophysics Program and Department of Chemistry, Stanford University, Stanford, CA, USA.
3
Bioengineering Department, Stanford University, Stanford, CA, USA.
4
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.

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 (σ1) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ1 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 (σ1) receptor.

KEYWORDS:

Amino acids; Bis-nucleophile; Multicomponent reaction; Sigma-1 receptor; Spiro-2,6-dioxopyrazine

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