4LZ7

Crystal structures of GLuR2 ligand-binding-domain in complex with glutamate and positive allosteric modulators

Summary for 4LZ7

• Entry DOI: 10.2210/pdb4lz7/pdb
• Related: 4LZ5 4LZ8
• Descriptor: Glutamate receptor 2, ZINC ION, GLUTAMIC ACID, ... (5 entities in total)
• Functional Keywords: ampa receptor, allosteric modulator, transport protein
• Biological source: Rattus norvegicus (brown rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 3
• Total formula weight: 92410.65

Authors

Pandit, J. (deposition date: 2013-07-31, release date: 2013-12-04, Last modification date: 2024-11-06)

Primary citation

Patel, N.C.,Schwarz, J.,Hou, X.J.,Hoover, D.J.,Xie, L.,Fliri, A.J.,Gallaschun, R.J.,Lazzaro, J.T.,Bryce, D.K.,Hoffmann, W.E.,Hanks, A.N.,McGinnis, D.,Marr, E.S.,Gazard, J.L.,Hajos, M.,Scialis, R.J.,Hurst, R.S.,Shaffer, C.L.,Pandit, J.,O'Donnell, C.J.
Discovery and Characterization of a Novel Dihydroisoxazole Class of alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Potentiators.
J.Med.Chem., 56:9180-9191, 2013

PubMed Abstract: Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.

PubMed: 24215237
DOI: 10.1021/jm401274b

Experimental method

X-RAY DIFFRACTION (2.1 Å)