PMID- 28831019
OWN - NLM
STAT- MEDLINE
DCOM- 20180110
LR  - 20180110
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 10
IP  - 493
DP  - 2017 Aug 22
TI  - Multiplex quantitative assays indicate a need for reevaluating reported 
      small-molecule TrkB agonists.
LID - eaal1670 [pii]
LID - 10.1126/scisignal.aal1670 [doi]
AB  - Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related 
      kinase B (TrkB), have emerged as key regulators of brain plasticity and represent 
      disease-modifying targets for several brain disorders, including Alzheimer's 
      disease and major depressive disorder. Because of poor pharmacokinetic properties 
      of BDNF, the interest in small-molecule TrkB agonists and modulators is high. 
      Several compounds have been reported to act as TrkB agonists, and their 
      increasing use in various nervous system disorder models creates the perception 
      that these are reliable probes. To examine key pharmacological parameters of 
      these compounds in detail, we have developed and optimized a series of 
      complementary quantitative assays that measure TrkB receptor activation, 
      TrkB-dependent downstream signaling, and gene expression in different cellular 
      contexts. Although BDNF and other neurotrophic factors elicited robust and 
      dose-dependent receptor activation and downstream signaling, we were unable to 
      reproduce these activities using the reported small-molecule TrkB agonists. Our 
      findings indicate that experimental results obtained with these compounds must be 
      carefully interpreted and highlight the challenge of developing reliable 
      pharmacological activators of this key molecular target.
CI  - Copyright (c) 2017 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Boltaev, Umed
AU  - Boltaev U
AUID- ORCID: 0000-0002-0040-7228
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA.
AD  - NeuroTechnology Center at Columbia University, New York, NY 10027, USA.
FAU - Meyer, Yves
AU  - Meyer Y
AUID- ORCID: 0000-0003-2540-1719
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA.
FAU - Tolibzoda, Farangis
AU  - Tolibzoda F
AUID- ORCID: 0000-0003-2807-4645
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA.
AD  - NeuroTechnology Center at Columbia University, New York, NY 10027, USA.
FAU - Jacques, Teresa
AU  - Jacques T
AUID- ORCID: 0000-0002-4371-8325
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA.
FAU - Gassaway, Madalee
AU  - Gassaway M
AUID- ORCID: 0000-0002-7601-413X
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA.
AD  - NeuroTechnology Center at Columbia University, New York, NY 10027, USA.
FAU - Xu, Qihong
AU  - Xu Q
AUID- ORCID: 0000-0002-2606-3216
AD  - Stanley Center for Psychiatric Research, Broad Institute of Massachusetts 
      Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142, 
      USA.
FAU - Wagner, Florence
AU  - Wagner F
AD  - Stanley Center for Psychiatric Research, Broad Institute of Massachusetts 
      Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142, 
      USA.
FAU - Zhang, Yan-Ling
AU  - Zhang YL
AD  - Stanley Center for Psychiatric Research, Broad Institute of Massachusetts 
      Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142, 
      USA.
FAU - Palmer, Michelle
AU  - Palmer M
AD  - Stanley Center for Psychiatric Research, Broad Institute of Massachusetts 
      Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142, 
      USA.
FAU - Holson, Edward
AU  - Holson E
AD  - Stanley Center for Psychiatric Research, Broad Institute of Massachusetts 
      Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142, 
      USA.
FAU - Sames, Dalibor
AU  - Sames D
AUID- ORCID: 0000-0001-6911-2260
AD  - Department of Chemistry, Columbia University, New York, NY 10027, USA. 
      sames@chem.columbia.edu.
AD  - NeuroTechnology Center at Columbia University, New York, NY 10027, USA.
LA  - eng
PT  - Journal Article
DEP - 20170822
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (7,8-dihydroxyflavanone)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Flavanones)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Small Molecule Libraries)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.1 (tropomyosin-related kinase-B, human)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cells, Cultured
MH  - Embryo, Mammalian/cytology/drug effects/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flavanones/pharmacology
MH  - High-Throughput Screening Assays
MH  - Humans
MH  - Membrane Glycoproteins/*agonists/metabolism
MH  - Neuroblastoma/*drug therapy/metabolism/pathology
MH  - Neurons/cytology/*drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Rats
MH  - Receptor, trkB/*agonists/metabolism
MH  - *Signal Transduction
MH  - Small Molecule Libraries/*pharmacology
EDAT- 2017/08/24 06:00
MHDA- 2018/01/11 06:00
CRDT- 2017/08/24 06:00
PHST- 2017/08/24 06:00 [entrez]
PHST- 2017/08/24 06:00 [pubmed]
PHST- 2018/01/11 06:00 [medline]
AID - 10/493/eaal1670 [pii]
AID - 10.1126/scisignal.aal1670 [doi]
PST - epublish
SO  - Sci Signal. 2017 Aug 22;10(493):eaal1670. doi: 10.1126/scisignal.aal1670.