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J Med Chem. 2018 Mar 8;61(5):2124-2130. doi: 10.1021/acs.jmedchem.8b00099. Epub 2018 Feb 26.

( S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation.

Author information

1
Department of Biotechnology, Chemistry and Pharmacy, (DoE 2018-2022) NatSynDrugs , University of Siena , Via A. Moro 2 , 53100 Siena , Italy.
2
Department of Pharmacy , University of Napoli Federico II , Via D. Montesano 49 , 80131 Napoli , Italy.
3
Department of Medicine, Surgery and Neuroscience , University of Siena , Viale M. Bracci 16 , 53100 Siena , Italy.
4
School of Pharmacy, Faculty of Health Sciences , University of Eastern Finland , 70211 Kuopio , Finland.
5
Department of Drug Design and Pharmacology , University of Copenhagen , Jagtvej 162 , DK-2100 Copenhagen , Denmark.

Abstract

Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).

PMID:
29451794
DOI:
10.1021/acs.jmedchem.8b00099
[Indexed for MEDLINE]

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