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).
(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 / Brogi, S., Brindisi, M., Butini, S., Kshirsagar, G.U., Maramai, S., Chemi, G., Gemma, S., Campiani, G., Novellino, E., Fiorenzani, P., Pinassi, J., Aloisi, A.M., Gynther, M., Venskutonytė, R., Han, L., Frydenvang, K., Kastrup, J.S., Pickering, D.S.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:5(2018), pp. 2124-2130. [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
Brindisi, MargheritaSecondo
;Novellino, Ettore;
2018
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).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
