Journal article
CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured
Cephalalgia, Vol.38(3), pp.437-451
03/2018
DOI: 10.1177/0333102417691762
PMCID: PMC5494006
PMID: 28165287
Abstract
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\n) 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\nreceptors 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\nreceptors 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\nreceptor, 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.
Details
- Title: Subtitle
- CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured
- Creators
- Christopher S Walker - 2 Centre for Brain Research, University of Auckland, Auckland, New ZealandAnn C Raddant - 3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USAMichael J Woolley - 4 Institute of Clinical Studies, University of Birmingham, Edgbaston, Birmingham, UKAndrew F Russo - 5 Department of Neurology, University of Iowa; Veterans Affairs Medical Center, Iowa City, IA, USADebbie L Hay - 2 Centre for Brain Research, University of Auckland, Auckland, New Zealand
- Resource Type
- Journal article
- Publication Details
- Cephalalgia, Vol.38(3), pp.437-451
- DOI
- 10.1177/0333102417691762
- PMID
- 28165287
- PMCID
- PMC5494006
- NLM abbreviation
- Cephalalgia
- ISSN
- 0333-1024
- eISSN
- 1468-2982
- Publisher
- England
- Grant note
- R01 NS075599 / NINDS NIH HHS\nF31 NS074728 / NINDS NIH HHS
- Language
- English
- Date published
- 03/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
- Record Identifier
- 9984070381702771
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