5BUU

Crystal structure of the GluA2 ligand-binding domain (L483Y-N754S) in complex with glutamate and BPAM-321 at 2.07 A resolution

Summary for 5BUU

• Entry DOI: 10.2210/pdb5buu/pdb
• Related: 3il1 4n07
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, (3R)-7-chloro-2,3,4-trimethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, GLUTAMIC ACID, ... (6 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, glua2 l483y-n754s, bpam-321 positive allosteric modulation, membrane protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 2
• Total formula weight: 60095.75

Authors

Larsen, A.P.,Tapken, D.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2015-06-04, release date: 2016-02-17, Last modification date: 2024-11-06)

Primary citation

Larsen, A.P.,Francotte, P.,Frydenvang, K.,Tapken, D.,Goffin, E.,Fraikin, P.,Caignard, D.H.,Lestage, P.,Danober, L.,Pirotte, B.,Kastrup, J.S.
Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors.
Acs Chem Neurosci, 7:378-390, 2016

PubMed Abstract: Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7-4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency.

PubMed: 26771108
DOI: 10.1021/acschemneuro.5b00318

Experimental method

X-RAY DIFFRACTION (2.07 Å)