Synthesis of new isoxazoline-based acidic amino acids and investigation of their affinity and selectivity profile at ionotropic glutamate receptors

• Published in: European journal of medicinal chemistry Vol. 46; no. 2; pp. 787 - 793
• Main Authors: Pinto, Andrea, Conti, Paola, Grazioso, Giovanni, Tamborini, Lucia, Madsen, Ulf, Nielsen, Birgitte, De Micheli, Carlo
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.02.2011; Elsevier
• Subjects: 1,3-Dipolar cycloaddition; Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacology; Binding Sites - drug effects; Biological and medical sciences; Chemistry, Medicinal; Glutamatergic system (aspartate and other excitatory aminoacids); Glutamic acid; Ionotropic Glu receptors; Isoxazoles - chemistry; Isoxazoline; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptors, Ionotropic Glutamate - chemistry; Receptors, Ionotropic Glutamate - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Glutamic acid; 1,3-Dipolar cycloaddition; Ionotropic Glu receptors; Isoxazoline; CYCLOADDITION; COMPLEX; DESIGN; AMPA; ANTAGONIST; MODEL; BINDING; Ionotropic receptor; Stereoisomer; Isoxazole derivatives; Active site; Glutamate receptor; Selectivity; Modeling; Biological activity; α-Aminoacid; AMPA receptor; Aminoacid; Molecular model; Affinity; NMDA receptor; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.12.020

The synthesis of four new isoxazoline-based amino acids being analogues of previously described glutamate receptor ligands is reported and their affinity for ionotropic glutamate receptors is analyzed in comparison with that of selected model compounds. Molecular modelling investigations have been carried out to rationalize the interaction with the NMDA receptors. New isoxazoline-based acidic amino acids have been synthesized and tested at ionotropic glutamate receptors. Molecular modelling investigations have been carried out to rationalize the interaction with the NMDA receptors. [Display omitted] ► Glutamic acid is the main excitatory neurotransmitter in the CNS. ► NMDA receptors are potential therapeutic targets for treatment of CNS disorders. ► New competitive NMDA receptor antagonists have been synthesized and tested. ► The mode of interaction with NMDA/NR2A subunit has been proposed.