5YBF

Crystal structure of the GluA2o LBD in complex with glutamate and HBT1

Summary for 5YBF

• Entry DOI: 10.2210/pdb5ybf/pdb
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, GLUTAMIC ACID, 2-[2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanoylamino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, ... (6 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, allosteric modulation complex, membrane protein, transport protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P42262
• Total number of polymer chains: 6
• Total formula weight: 178841.11

Authors

Sogabe, S.,Igaki, S.,Hirokawa, A.,Zama, Y.,Lane, W.,Snell, G. (deposition date: 2017-09-04, release date: 2018-01-17, Last modification date: 2024-10-30)

Primary citation

Kunugi, A.,Tajima, Y.,Kuno, H.,Sogabe, S.,Kimura, H.
HBT1, a Novel AMPA Receptor Potentiator with Lower Agonistic Effect, Avoided Bell-Shaped Response in In Vitro BDNF Production.
J. Pharmacol. Exp. Ther., 364:377-389, 2018

PubMed Abstract: -Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (AMPA-R) potentiators with brain-derived neurotrophic factor (BDNF)-induction potential could be promising as therapeutic drugs for neuropsychiatric and neurologic disorders. However, AMPA-R potentiators such as LY451646 have risks of narrow bell-shaped responses in pharmacological effects, including in vivo BDNF induction. Interestingly, LY451646 and LY451395, other AMPA-R potentiators, showed agonistic effects and exhibited bell-shaped responses in the BDNF production in primary neurons. We hypothesized that the agonistic property is related to the bell-shaped response and endeavored to discover novel AMPA-R potentiators with lower agonistic effects. LY451395 showed an agonistic effect in primary neurons, but not in a cell line expressing AMPA-Rs, in Ca influx assays; thus, we used a Ca influx assay in primary neurons and, from a chemical library, discovered two AMPA-R potentiators with lower agonistic effects: 2-(((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (HBT1) and (3S)-1-(4-tert-butylphenyl)-N-((1R)-2-(dimethylamino)-1-phenylethyl)-3-isobutyl-2-oxopyrrolidine-3-carboxamide (OXP1). In a patch-clamp study using primary neurons, HBT1 showed little agonistic effect, whereas both LY451395 and OXP1 showed remarkable agonistic effects. HBT1, but not OXP1, did not show remarkable bell-shaped response in BDNF production in primary neurons. HBT1 bound to the ligand-binding domain (LBD) of AMPA-R in a glutamate-dependent manner. The mode of HBT1 and LY451395 binding to a pocket in the LBD of AMPA-R differed: HBT1, but not LY451395, formed hydrogen bonds with S518 in the LBD. OXP1 may bind to a cryptic binding pocket on AMPA-R. Lower agonistic profile of HBT1 may associate with its lower risks of bell-shaped responses in BDNF production in primary neurons.

PubMed: 29298820
DOI: 10.1124/jpet.117.245050

Experimental method

X-RAY DIFFRACTION (1.5 Å)