4X48

Crystal structure of GluR2 ligand-binding core

Summary for 4X48

• Entry DOI: 10.2210/pdb4x48/pdb
• Related: 4LZ5 4LZ7 4LZ8
• Descriptor: Glutamate receptor 2, GLUTAMIC ACID, ZINC ION, ... (5 entities in total)
• Functional Keywords: ampa receptor, allosteric modulator, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 3
• Total formula weight: 92584.94

Authors

Pandit, J. (deposition date: 2014-12-02, release date: 2015-05-06, Last modification date: 2024-10-16)

Primary citation

Shaffer, C.L.,Patel, N.C.,Schwarz, J.,Scialis, R.J.,Wei, Y.,Hou, X.J.,Xie, L.,Karki, K.,Bryce, D.K.,Osgood, S.M.,Hoffmann, W.E.,Lazzaro, J.T.,Chang, C.,McGinnis, D.F.,Lotarski, S.M.,Liu, J.,Obach, R.S.,Weber, M.L.,Chen, L.,Zasadny, K.R.,Seymour, P.A.,Schmidt, C.J.,Hajos, M.,Hurst, R.S.,Pandit, J.,O'Donnell, C.J.
The Discovery and Characterization of the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).
J.Med.Chem., 58:4291-4308, 2015

PubMed Abstract: A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

PubMed: 25905800
DOI: 10.1021/acs.jmedchem.5b00300

Experimental method

X-RAY DIFFRACTION (1.89 Å)