Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs
| Autor: | Maria Carmela Fulco, Antonio Macchiarulo, Christian Thomsen, Julia Gafarova, Søren Møller Nielsen, Maura Marinozzi, Gianluca Giorgi, Roberto Pellicciari, Michaela Serpi |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cyclopropanes
Models Molecular Stereochemistry Glycine Molecular Conformation AMPA receptor In Vitro Techniques Crystallography X-Ray Receptors Metabotropic Glutamate Receptors N-Methyl-D-Aspartate Cell Line Structure-Activity Relationship chemistry.chemical_compound Receptors Kainic Acid Cricetinae glutamate excitatory amino acids Drug Discovery Animals Receptors AMPA Sulfones Receptor Homocysteine chemistry.chemical_classification Principal Component Analysis Chemistry Glutamate receptor Brain Stereoisomerism Homocysteic acid Rats Amino acid Biochemistry Docking (molecular) Excitatory postsynaptic potential Thermodynamics Molecular Medicine NMDA receptor |
| Popis: | Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS. |
| Databáze: | OpenAIRE |
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