CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.
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 (AMY1) 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 AMY1receptors 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 AMY1receptors 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 AMY1receptor, 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.
1 School of Biological Sciences, University of Auckland, Auckland, New Zealand.|2 Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Christopher S
CS
Walker
3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
Ann C
AC
Raddant
4 Institute of Clinical Studies, University of Birmingham, Edgbaston, Birmingham, UK.
Michael J
MJ
Woolley
3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.|5 Department of Neurology, University of Iowa; Veterans Affairs Medical Center, Iowa City, IA, USA.
Andrew F
AF
Russo
1 School of Biological Sciences, University of Auckland, Auckland, New Zealand.|2 Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Debbie L
DL
Hay
D000818:Animals; D019556:COS Cells; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D012668:Trigeminal Ganglion / Q000187:drug effects
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides; D010879:Piperazines; D011799:Quinazolines; D018015:Receptors, Calcitonin Gene-Related Peptide; D058287:Receptors, Islet Amyloid Polypeptide; C406305:olcegepant
Amylin 1 (AMY1); CREB; bias; calcitonin gene-related peptide (CGRP); migraine; pain; trigeminal ganglia