Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

作者：Skold Niklas; Nielsen Birgitte; Olsen Jacob; Han Liwei; Olsen Lars; Madsen Ulf; Kristensen Jesper L; Pickering Darryl S; Johansen Tommy N^*

来源：Bioorganic & Medicinal Chemistry, 2014, 22(19): 5368-5377.

DOI：10.1016/j.bmc.2014.07.045

• Glutamate receptors
• GluK1 antagonist
• GluK3 antagonist
• 2-Carboxyethylphenylalanine
• Structure based design
• SAR
• Negishi reaction

In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of ( S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea ( compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.

• 出版日期2014-10-1