( 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

Simone Brogi; Margherita Brindisi; Stefania Butini; Giridhar U Kshirsagar; Samuele Maramai; Giulia Chemi; Sandra Gemma; Giuseppe Campiani; Ettore Novellino; Paolo Fiorenzani; Jessica Pinassi; Anna Maria Aloisi; Mikko Gynther; Raminta Venskutonytė; Liwei Han; Karla Frydenvang; Jette Sandholm Kastrup; Darryl S Pickering

doi:10.1021/acs.jmedchem.8b00099

( 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

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

Authors

Simone Brogi¹, Margherita Brindisi¹, Stefania Butini¹, Giridhar U Kshirsagar¹, Samuele Maramai¹, Giulia Chemi¹, Sandra Gemma¹, Giuseppe Campiani¹, Ettore Novellino², Paolo Fiorenzani³, Jessica Pinassi³, Anna Maria Aloisi³, Mikko Gynther⁴, Raminta Venskutonytė⁵, Liwei Han⁵, Karla Frydenvang⁵, Jette Sandholm Kastrup⁵, Darryl S Pickering⁵

Affiliations

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.

PMID: 29451794
DOI: 10.1021/acs.jmedchem.8b00099

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / chemistry
Animals
Crystallography, X-Ray
GluK3 Kainate Receptor
Ligands
Protein Binding
Receptors, AMPA
Receptors, Kainic Acid / agonists
Receptors, Kainic Acid / antagonists & inhibitors
Receptors, Kainic Acid / chemistry*
Receptors, Kainic Acid / metabolism
Structure-Activity Relationship
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / analogs & derivatives*
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry

Substances

Analgesics
Gluk1 kainate receptor
Ligands
Receptors, AMPA
Receptors, Kainic Acid
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid