PMID- 31654653
OWN - NLM
STAT- MEDLINE
DCOM- 20200721
LR  - 20200721
IS  - 1873-5177 (Electronic)
IS  - 0091-3057 (Linking)
VI  - 187
DP  - 2019 Dec
TI  - TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting 
      effects in mice.
PG  - 172794
LID - S0091-3057(19)30458-7 [pii]
LID - 10.1016/j.pbb.2019.172794 [doi]
AB  - Orexin-producing neurons in the lateral hypothalamus are a critical regulator of 
      sleep/wake states, and their loss is associated with narcolepsy type 1 (NT1). 
      Orexin peptides act on two G protein-coupled receptors: orexin 1 receptor (OX1R) 
      and orexin 2 receptor (OX2R). OX2R knockout (KO) mice, but not OX1R KO mice, 
      showed clear narcolepsy-like phenotypes, including fragmented sleep-wake cycles. 
      Moreover, OX2R-selective antagonists have been shown to induce sleepiness in 
      mice, and activation of OX2R has been reported to increase wakefulness. In this 
      study, we characterized in vitro and in vivo profiles of a novel, highly 
      selective OX2R agonist, TAK-925 [methyl 
      (2R,3S)-3-[(methylsulfonyl)amino]-2-[(cis-4-phenylcyclohexyl)oxy]methylpiperidine-1-carboxylate]. 
      TAK-925 activated human recombinant OX2R with 50% effective concentration value 
      of 5.5 nM, and showed >5,000-fold selectivity over OX1R in calcium mobilization 
      assays. TAK-925 induced OX2R-downstream signals similar to those displayed by 
      orexin peptides in Chinese hamster ovary cells stably expressing human OX2R. In 
      an electrophysiological study, TAK-925 activated physiological OX2R on 
      histaminergic neurons in the mouse tuberomammillary nucleus (TMN). Subcutaneous 
      (SC) administration of TAK-925 also modulated neuronal activity in various brain 
      regions, including TMN, as measured by an immunohistochemical analysis using an 
      anti-c-fos antibody. TAK-925 (SC) increased wakefulness in wild-type mice, but 
      not in OX2R KO mice, during their sleep phase, demonstrating that a highly 
      selective OX2R agonist can increase wakefulness in mice via OX2R activation. 
      TAK-925 may have therapeutic potential to reduce hypersomnia in multiple 
      disorders including NT1.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Yukitake, Hiroshi
AU  - Yukitake H
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Fujimoto, Tatsuhiko
AU  - Fujimoto T
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Ishikawa, Takashi
AU  - Ishikawa T
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Suzuki, Atsushi
AU  - Suzuki A
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Shimizu, Yuji
AU  - Shimizu Y
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Rikimaru, Kentaro
AU  - Rikimaru K
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Ito, Mitsuhiro
AU  - Ito M
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Suzuki, Motohisa
AU  - Suzuki M
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan.
FAU - Kimura, Haruhide
AU  - Kimura H
AD  - Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company 
      Limited, Fujisawa, Japan. Electronic address: haruhide.kimura@takeda.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191022
PL  - United States
TA  - Pharmacol Biochem Behav
JT  - Pharmacology, biochemistry, and behavior
JID - 0367050
RN  - 0 (Cd200r1 protein, mouse)
RN  - 0 (HCRTR2 protein, human)
RN  - 0 (Orexin Receptors)
RN  - 0 (Orexins)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Cricetulus
MH  - Humans
MH  - Hypothalamic Area, Lateral/cytology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Narcolepsy/drug therapy
MH  - Neurons/drug effects/metabolism
MH  - Orexin Receptors/*agonists/genetics/metabolism
MH  - Orexins/metabolism
MH  - Sleep/*drug effects/genetics
MH  - Transfection
MH  - Wakefulness/*drug effects/genetics
OTO - NOTNLM
OT  - Hypersomnia
OT  - Narcolepsy
OT  - Orexin
OT  - Orexin 2 receptor
OT  - Orexin 2 receptor agonist
OT  - TAK-925
EDAT- 2019/10/28 06:00
MHDA- 2020/07/22 06:00
CRDT- 2019/10/27 06:00
PHST- 2019/09/11 00:00 [received]
PHST- 2019/10/01 00:00 [revised]
PHST- 2019/10/01 00:00 [accepted]
PHST- 2019/10/28 06:00 [pubmed]
PHST- 2020/07/22 06:00 [medline]
PHST- 2019/10/27 06:00 [entrez]
AID - S0091-3057(19)30458-7 [pii]
AID - 10.1016/j.pbb.2019.172794 [doi]
PST - ppublish
SO  - Pharmacol Biochem Behav. 2019 Dec;187:172794. doi: 10.1016/j.pbb.2019.172794. 
      Epub 2019 Oct 22.