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Bioorg Med Chem. 2016 Nov 15;24(22):5741-5747. doi: 10.1016/j.bmc.2016.09.029. Epub 2016 Sep 12.

Synthesis and pharmacological evaluation of conformationally constrained glutamic acid higher homologues.

Author information

1
Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
2
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen OE, Denmark.
3
Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy. Electronic address: andrea.pinto@unimi.it.

Abstract

Homologation of glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. In the present work, starting from two potent and selective unnatural amino acids previously developed by us, we investigated the effects on the activity/selectivity profile produced by a further increase in the distance between the amino acidic moiety and the distal carboxylate group. Interestingly, the insertion of an aromatic ring as a spacer produced a low micromolar affinity NMDA ligand that might represent a lead for the development of a new class of NMDA antagonists.

KEYWORDS:

1,3-Dipolar cycloaddition; Amino acid; N-Methyl-d-aspartate receptor; l-Glutamic acid; Δ(2)-Isoxazoline

PMID:
27658797
DOI:
10.1016/j.bmc.2016.09.029
[Indexed for MEDLINE]

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