PMID- 29298820
OWN - NLM
STAT- MEDLINE
DCOM- 20190528
LR  - 20210315
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 364
IP  - 3
DP  - 2018 Mar
TI  - HBT1, a Novel AMPA Receptor Potentiator with Lower Agonistic Effect, Avoided 
      Bell-Shaped Response in In Vitro BDNF Production.
PG  - 377-389
LID - 10.1124/jpet.117.245050 [doi]
AB  - alpha-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(2+) influx 
      assays; thus, we used a Ca(2+) 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.
CI  - Copyright (c) 2018 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Kunugi, Akiyoshi
AU  - Kunugi A
AD  - Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
FAU - Tajima, Yasukazu
AU  - Tajima Y
AD  - Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
FAU - Kuno, Haruhiko
AU  - Kuno H
AD  - Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
FAU - Sogabe, Satoshi
AU  - Sogabe S
AD  - Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
FAU - Kimura, Haruhide
AU  - Kimura H
AD  - Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan 
      haruhide.kimura@takeda.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180103
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (AMPA receptor potentiator HBT1)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (LY 404187)
RN  - 0 
      (N-((2-(4'-(2-(methylsulfonyl)amino)ethyl)(1,1'-biphenyl)-4-yl)propyl)-2-propanesulfonamide)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Sulfonamides)
RN  - 0 (Thiophenes)
RN  - 073790YQ2G (benzothiophene)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Biphenyl Compounds/pharmacology
MH  - Brain-Derived Neurotrophic Factor/*biosynthesis
MH  - Calcium/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Neurons/drug effects/metabolism
MH  - Pyrazoles/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/*agonists
MH  - Sulfonamides/pharmacology
MH  - Thiophenes/*pharmacology
EDAT- 2018/01/05 06:00
MHDA- 2019/05/29 06:00
CRDT- 2018/01/05 06:00
PHST- 2017/09/11 00:00 [received]
PHST- 2017/12/28 00:00 [accepted]
PHST- 2018/01/05 06:00 [pubmed]
PHST- 2019/05/29 06:00 [medline]
PHST- 2018/01/05 06:00 [entrez]
AID - jpet.117.245050 [pii]
AID - 10.1124/jpet.117.245050 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2018 Mar;364(3):377-389. doi: 10.1124/jpet.117.245050. Epub 
      2018 Jan 3.