PMID- 28165287
OWN - NLM
STAT- MEDLINE
DCOM- 20190125
LR  - 20211204
IS  - 1468-2982 (Electronic)
IS  - 0333-1024 (Print)
IS  - 0333-1024 (Linking)
VI  - 38
IP  - 3
DP  - 2018 Mar
TI  - CGRP receptor antagonist activity of olcegepant depends on the signalling pathway 
      measured.
PG  - 437-451
LID - 10.1177/0333102417691762 [doi]
AB  - Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in 
      the trigeminovascular system and is believed to play an important role in 
      migraine. CGRP activates two receptors that are both present in the 
      trigeminovascular system; the CGRP receptor and the amylin 1 (AMY(1)) receptor. 
      CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant 
      (MK-0974), can treat migraine. This study aimed to determine the effectiveness of 
      these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) 
      neurons and transfected CGRP and AMY(1) receptors in Cos7 cells, to better 
      understand their mechanism of action. Methods CGRP stimulation of four 
      intracellular signalling molecules relevant to pain (cAMP, CREB, p38 and ERK) 
      were examined in rat TG neurons and compared to transfected CGRP and AMY(1) 
      receptors in Cos7 cells. Results In TG neurons, olcegepant displayed 
      signal-specific differences in antagonism of CGRP responses. This effect was also 
      evident in transfected Cos7 cells, where olcegepant blocked CREB phosphorylation 
      more potently than expected at the AMY(1) receptor, suggesting that the affinity 
      of this antagonist can be dependent on the signalling pathway activated. 
      Conclusions CGRP receptor antagonist activity appears to be assay-dependent. 
      Thus, these molecules may not be as selective for the CGRP receptor as commonly 
      reported.
FAU - Walker, Christopher S
AU  - Walker CS
AD  - 1 School of Biological Sciences, University of Auckland, Auckland, New Zealand.
AD  - 2 Centre for Brain Research, University of Auckland, Auckland, New Zealand.
FAU - Raddant, Ann C
AU  - Raddant AC
AD  - 3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa 
      City, IA, USA.
FAU - Woolley, Michael J
AU  - Woolley MJ
AD  - 4 Institute of Clinical Studies, University of Birmingham, Edgbaston, Birmingham, 
      UK.
FAU - Russo, Andrew F
AU  - Russo AF
AD  - 3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa 
      City, IA, USA.
AD  - 5 Department of Neurology, University of Iowa; Veterans Affairs Medical Center, 
      Iowa City, IA, USA.
FAU - Hay, Debbie L
AU  - Hay DL
AD  - 1 School of Biological Sciences, University of Auckland, Auckland, New Zealand.
AD  - 2 Centre for Brain Research, University of Auckland, Auckland, New Zealand.
LA  - eng
GR  - F31 NS074728/NS/NINDS NIH HHS/United States
GR  - R01 NS075599/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170206
PL  - England
TA  - Cephalalgia
JT  - Cephalalgia : an international journal of headache
JID - 8200710
RN  - 0 (Calcitonin Gene-Related Peptide Receptor Antagonists)
RN  - 0 (Dipeptides)
RN  - 0 (Piperazines)
RN  - 0 (Quinazolines)
RN  - 0 (Receptors, Calcitonin Gene-Related Peptide)
RN  - 0 (Receptors, Islet Amyloid Polypeptide)
RN  - WOA5J8TX6M (olcegepant)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Calcitonin Gene-Related Peptide Receptor Antagonists/*pharmacology
MH  - Chlorocebus aethiops
MH  - Dipeptides/*pharmacology
MH  - Humans
MH  - Neurons/*drug effects
MH  - Piperazines
MH  - Quinazolines/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Calcitonin Gene-Related Peptide/drug effects
MH  - Receptors, Islet Amyloid Polypeptide/antagonists & inhibitors
MH  - Signal Transduction/*drug effects/physiology
MH  - Transfection
MH  - Trigeminal Ganglion/drug effects
PMC - PMC5494006
MID - NIHMS860184
OTO - NOTNLM
OT  - Amylin 1 (AMY1)
OT  - CREB
OT  - bias
OT  - calcitonin gene-related peptide (CGRP)
OT  - migraine
OT  - pain
OT  - trigeminal ganglia
COIS- Declaration of conflicting interests The authors declared no potential conflicts 
      of interest with respect to the research, authorship, and/or publication of this 
      article.
EDAT- 2017/02/07 06:00
MHDA- 2019/01/27 06:00
PMCR- 2019/03/01
CRDT- 2017/02/07 06:00
PHST- 2017/02/07 06:00 [pubmed]
PHST- 2019/01/27 06:00 [medline]
PHST- 2017/02/07 06:00 [entrez]
PHST- 2019/03/01 00:00 [pmc-release]
AID - 10.1177/0333102417691762 [doi]
PST - ppublish
SO  - Cephalalgia. 2018 Mar;38(3):437-451. doi: 10.1177/0333102417691762. Epub 2017 Feb 
      6.